The IL-6 rs1800795 and rs1800796 polymorphisms are associated with coronary artery disease risk.
Lu Shuai,Wang Ya,Wang Yijun,Hu Jing,Di Wu,Liu Shuangye,Zeng Xiaohui,Yu Guo,Wang Yan,Wang Zhaohui
Journal of cellular and molecular medicine
Studies examining the associations between the interleukin-6 (IL-6) rs1800795 and rs1800796 gene polymorphisms and risk of coronary artery disease (CAD) remain controversial. Our aim was to evaluate the accurately determine role of these two polymorphisms in CAD risk. PubMed, Embase, VIP, Wan fang and China National Knowledge Infrastructure databases were searched. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The trial sequential analysis (TSA) was conducted, and bioinformatics tools were employed. A total of thirty-seven articles were obtained. For the IL-6 rs1800795 polymorphism, 9411 CAD patients and 3161 controls were included, 4720 patients with CAD, and 5000 controls were included for the IL-6 rs1800796 polymorphism. In the pooled analysis, significant associations were only observed for the rs1800796 polymorphism (allelic: OR [95%CI] = 1.28 [1.13, 1.44], dominant: OR [95%CI] = 1.35 [1.17, 1.57], recessive: OR [95%CI] = 1.35 [1.18, 1.55], heterozygote: OR [95%CI] = 1.26 [1.15, 1.37], homozygote: OR [95%CI] = 1.62 [1.23, 2.13]). Significant associations were detected in the Asian and Mongoloid populations and 'more than 500' subgroup for the rs1800795 polymorphism. TSA confirmed the true-positive results for the rs1800796 polymorphism. The bioinformatics analysis showed that the two polymorphisms played important roles in the gene transcription. The IL-6 rs1800796 polymorphism is associated with an increased susceptibility to CAD and is a risk factor for CAD. The IL-6 rs1800795 polymorphism is associated with an increased risk of CAD in Asians, particularly in Chinese, and a decreased risk of CAD in an African population is remarkably observed.
10.1111/jcmm.15246
Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.
Zhu Lin,Giunzioni Ilaria,Tavori Hagai,Covarrubias Roman,Ding Lei,Zhang Youmin,Ormseth Michelle,Major Amy S,Stafford John M,Linton MacRae F,Fazio Sergio
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages. APPROACH AND RESULTS:Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression. CONCLUSIONS:Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.
10.1161/ATVBAHA.116.307736
Effect of ezetimibe on plasma adipokines: a systematic review and meta-analysis.
Dolezelova Eva,Stein Evan,Derosa Giuseppe,Maffioli Pamela,Nachtigal Petr,Sahebkar Amirhossein
British journal of clinical pharmacology
AIMS:Statins are known to influence the status of adipokines, which play a key role in the pathophysiology of cardiometabolic diseases. As the effect of ezetimibe as an add-on to statin therapy on the impact of statins on plasma adipokines levels is currently unclear, the aim of the present study was to investigate this through a meta-analysis of controlled trials. METHODS:A systematic review was performed, followed by a bibliographic search in PubMed, Medline, SCOPUS, Web of Science and Google Scholar databases. Quantitative data synthesis was performed using a fixed- or random-effects model (based on the level of interstudy heterogeneity) and the generic inverse variance weighting method. Effect sizes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS:Meta-analysis of 23 controlled trials did not suggest any significant effect of adding ezetimibe on top of statin therapy on plasma concentrations of adiponectin (SMD 0.34, 95% CI -0.28, 0.96; P = 0.288), leptin (SMD -0.75, 95% CI: -2.35, 0.85; P = 0.360), plasminogen activator inhibitor 1 (SMD -1.06, 95% CI: -2.81, 0.69; P = 0.236) and interleukin 6 (SMD 0.30, 95% CI: -0.08, 0.67; P = 0.124). However, significantly greater reductions in plasma concentrations of tumour necrosis factor α (TNF-α) (SMD -0.48, 95% CI -0.87, -0.08; P = 0.018) were achieved with ezetimibe/statin combination therapy. CONCLUSIONS:The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect compared with statin monotherapy. Owing to the emerging role of TNF-α in the pathogenesis of metabolic disorders, further investigations are required to unveil the translational relevance of this TNF-α-lowering effect.
10.1111/bcp.13250
Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices.
Tabit Corey E,Coplan Mitchell J,Chen Phetcharat,Jeevanandam Valluvan,Uriel Nir,Liao James K
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
BACKGROUND:Non-surgical bleeding (NSB) due to angiodysplasia is common in left ventricular assist device (LVAD) patients. Thrombin-induced angiopoietin-2 (Ang-2) expression in LVAD patients leads to altered angiogenesis and is associated with lower angiopoietin-1 (Ang-1) and increased NSB. However, the mechanism for decreased Ang-1, made by pericytes, is unknown and the origin of thrombin in LVAD patients is unclear. We hypothesized that high tumor necrosis factor-α (TNF-α) levels in LVAD patients induce pericyte apoptosis, tissue factor (TF) expression and vascular instability. METHODS:We incubated cultured pericytes with serum from patients with heart failure (HF), LVAD or orthotopic heart transplantation (OHT), with or without TNF-α blockade. We performed several measurements: Ang-1 expression was assessed by reverse transcript-polymerase chain reaction (RT-PCR) and pericyte death fluorescently; TF expression was assessed by RT-PCR in cultured endothelial cells incubated with patient plasma with or without TNF-α blockade; and TF expression was assessed in endothelial biopsy samples from these patients by immunofluorescence. We incubated cultured endothelial cells on Matrigel with patient serum with or without TNF-α blockade and determined tube formation by microscopy. RESULTS:Serum from LVAD patients had higher levels of TNF-α, suppressed Ang-1 expression in pericytes, and induced pericyte death, and there was accelerated endothelial tube formation compared with serum from patients without LVADs. TF was higher in both plasma and endothelial cells from LVAD patients, and plasma from LVAD patients induced more endothelial TF expression. All of these effects were reversed or reduced with TNF-α blockade. High levels of TNF-α were associated with increased risk of NSB. CONCLUSIONS:Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis and expression of TF and Ang-1.
10.1016/j.healun.2017.06.001
IL-1β (Interleukin-1β) and TNF-α (Tumor Necrosis Factor-α) Impact Abdominal Aortic Aneurysm Formation by Differential Effects on Macrophage Polarization.
Batra Rishi,Suh Melissa K,Carson Jeffrey S,Dale Matthew A,Meisinger Trevor M,Fitzgerald Matthew,Opperman Patrick J,Luo Jiangtao,Pipinos Iraklis I,Xiong Wanfen,Baxter B Timothy
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Abdominal aortic aneurysms are inflammatory in nature and are associated with some risk factors that also lead to atherosclerotic occlusive disease, most notably smoking. The purpose of our study was to identify differential cytokine expression in patients with abdominal aortic aneurysm and those with atherosclerotic occlusive disease. Based on this analysis, we further explored and compared the mechanism of action of IL (interleukin)-1β versus TNF-α (tumor necrosis factor-α) in abdominal aortic aneurysm formation. APPROACH AND RESULTS:IL-1β was differentially expressed in human plasma with lower levels detected in patients with abdominal aortic aneurysm compared with matched atherosclerotic controls. We further explored its mechanism of action using a murine model and cell culture. Genetic deletion of IL-1β and IL-1R did not inhibit aneurysm formation or decrease MMP (matrix metalloproteinase) expression. The effects of IL-1β deletion on M1 macrophage polarization were compared with another proinflammatory cytokine, TNF-α. Bone marrow-derived macrophages from IL-1β and TNF-α mice were polarized to an M1 phenotype. TNF-α deletion, but not IL-1β deletion, inhibited M1 macrophage polarization. Infusion of M1 polarized TNF-α macrophages inhibited aortic diameter growth; no inhibitory effect was seen in mice infused with M1 polarized IL-1β macrophages. CONCLUSIONS:Although IL-1β is a proinflammatory cytokine, its effects on aneurysm formation and macrophage polarization differ from TNF-α. The differential effects of IL-1β and TNF-α inhibition are related to M1/M2 macrophage polarization and this may account for the differences in clinical efficacy of IL-1β and TNF-α antibody therapies in management of inflammatory diseases.
10.1161/ATVBAHA.117.310333
Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α.
JAMA cardiology
Importance:Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision. Objective:To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. Design, Setting, and Participants:This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures:Circulating TNF-α concentration. Main Outcomes and Measures:DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results:The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (β [SE] = -0.01 [0.003]; P = 7.36 × 10-8), cg08122652 (β [SE] = -0.008 [0.002]; P = 2.24 × 10-7), and cg22930808(β [SE] = -0.01 [0.002]; P = 6.92 × 10-8); NLRC5 at cg16411857 (β [SE] = -0.01 [0.002]; P = 2.14 × 10-13) and cg07839457 (β [SE] = -0.02 [0.003]; P = 6.31 × 10-10); or ABO, at cg13683939 (β [SE] = 0.04 [0.008]; P = 1.42 × 10-7) and cg24267699 (β [SE] = -0.009 [0.002]; P = 1.67 × 10-7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10-5). Conclusions and Relevance:We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.
10.1001/jamacardio.2018.0510
Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-α-TNF Receptor-2 Pathway.
Wang Min,Zhang Chen,Tian Tian,Zhang Teng,Wang Ruiqing,Han Fengjiao,Zhong Chaoqin,Hua Mingqiang,Ma Daoxin
Frontiers in immunology
Acute myeloid leukemia (AML) harbors an immune suppression environment, featured by increased regulatory T cells (Tregs). The expression of tumor necrosis factor receptor-2 (TNFR2) on Tregs could be used to identify the maximally suppressive Treg population, and TNF-α furtherly promoted the expansion and function of Tregs TNFR2 in mice. However, the role of TNF-α has not been determined in AML patients. In view of high levels of TNF-α and Tregs in AML patients, we hypothesized that the increased frequency of Tregs may rely on TNF-α-TNFR2 pathway. We investigated the levels of TNFR2 Tregs and TNF-α secreted by T cells in peripheral blood (PB) of AML by flow cytometry and enzyme-linked immunosorbent assay, respectively. Our results showed the elevated plasma TNF-α in PB of newly diagnosed (ND) AML patients. The production of TNF-α by CD4 T cells, especially by T helper (Th)17 cells was remarkably higher in ND AML patients than in complete remission (CR) patients and healthy controls. Then, we found that the circulating frequencies of CD4CD25 Tregs and CD4CD25 Tregs in AML patients were elevated compared with those in healthy controls and CR patients. TNFR2 expression was much higher on Tregs in AML patients and was preferentially expressed on CD4CD25 T cells. Furthermore, we confirmed that, , the additional TNF-α can increase the frequency of Tregs through TNFR2 in both AML patients and healthy controls. Summarily, in AML patients, the abnormally elevated level of TNF-α secreted by CD4 T especially Th17 cells promoted the higher Tregs frequency the TNF-α-TNFR2 pathway.
10.3389/fimmu.2018.01274
Genetic variants of tumor necrosis factor-α and its levels: A correlation with dyslipidemia and type 2 diabetes susceptibility.
Patel Roma,Palit Sayantani Pramanik,Rathwa Nirali,Ramachandran A V,Begum Rasheedunnisa
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIM:Tumor necrosis factor-α (TNF-α) and its genetic variants are implicated in the development of type 2 diabetes (T2D) as a result of systemic inflammation, dyslipidemia, and insulin resistance. The aim of the present study was to investigate i) single nucleotide polymorphisms (SNPs) of TNF-α and its association with altered TNF-α transcript levels and plasma concentrations ii) free fatty acid (FFA) concentrations as a marker for dyslipidemia and its association with TNF-α and iii) genotype-phenotype correlation analysis in T2D patients. METHODS:Plasma and PBMCs were separated from venous blood of 478 diabetic patients and 502 age-matched non-diabetic individuals. Genomic DNA was isolated from PBMCs and RNA was isolated from PBMCs and adipose tissue samples. PCR-RFLP was used for genotyping and qPCR to estimate TNF-α levels. TNF-α and FFA concentrations were estimated from plasma samples by ELISA. RESULTS:Our study suggests: i) involvement of TNF-α -857 C/T in T2D patients (p < 0.0001), ii) 2.072 and 6.7 fold elevation in TNF-α transcript levels in patients' PBMCs and adipose tissues respectively, increased plasma TNF-α (p = 0.0122) particularly in obese patients (p = 0.0405), increased plasma FFA (p = 0.0215) and, iii) association of TNF-α -238 G/A with body mass index (BMI) (p = 0.0270) and, -857 C/T with fasting blood glucose (FBG) (p = 0.0122) and triglycerides (TG) (p = 0.0015). Correlation analysis suggests that TNF-α concentrations are positively correlated with BMI (r = 0.3, p = 0.04) and negatively correlated with HDL (r = -0.39, p = 0.001) while the FFA concentrations are positively correlated with BMI (r = 0.35, p = 0.0004). CONCLUSION:It can be concluded that the genetic variant of TNF-α along with elevated TNF-α and FFA concentrations play a role in the development of dyslipidemia which could be a potent risk factor towards T2D in Gujarat population.
10.1016/j.clnu.2018.06.962
Basolateral presence of the proinflammatory cytokine tumor necrosis factor -α and secretions from adipocytes and macrophages reduce intestinal sugar transport.
Castilla-Madrigal Rosa,Gil-Iturbe Eva,Sáinz Neira,Moreno-Aliaga María J,Lostao María Pilar
Journal of cellular physiology
We have previously demonstrated in Caco-2 cells that tumor necrosis factor-α (TNF-α) inhibits sugar uptake, acting from the apical membrane, by decreasing the expression of the Na -glucose cotransporter SGLT1 in the brush border membrane. The goal was to investigate the hypothesis that TNF-α from abdominal adipose tissue (adipocytes and macrophages) would decrease sugar and amino acid transport acting from the basolateral membrane of the enterocytes. TNF-α placed in the basal compartment of Caco-2 cells decreased α-methyl- d-glucose (αMG) and glutamine uptake. The apical medium derived from these Caco-2 cells apically placed in another set of cells, also reduced sugar and glutamine transport. Reverse-transcription polymerase chain reaction analysis demonstrated upregulation of TNF-α, IL-1β, and MCP1 expression in Caco-2 cells exposed to basal TNF-α. Similarly, αMG uptake was inhibited after Caco-2 cells were incubated, in the basal compartment, with medium from visceral human mesenchymal stem cells-derived adipocytes of overweight individuals. The apical medium collected from those Caco-2 cells, and placed in the upper side of other set of cells, also decreased sugar uptake. Basal presence of medium derived from lipopolysaccharide-activated macrophages and nonactivated macrophages decreased αMG uptake as well. Diet-induced obese mice showed an increase in the visceral adipose tissue surrounding the intestine. In this physiological condition, there was a reduction on αMG uptake in jejunal everted rings. Altogether, these results suggest that basolateral TNF-α, which can be produced by adipocytes and macrophages during obesity, would be able to activate TNF-α and other proinflammatory proteins expression in the small intestine and diminish intestinal sugar and amino acids transport.
10.1002/jcp.27216
Proinflammatory Mediators, IL (Interleukin)-1β, TNF (Tumor Necrosis Factor) α, and Thrombin Directly Induce Capillary Tube Regression.
Koller Gretchen M,Schafer Christopher,Kemp Scott S,Aguera Kalia N,Lin Prisca K,Forgy Joshua C,Griffin Courtney T,Davis George E
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:In this work, we examine the molecular basis for capillary tube regression and identify key proregressive factors, signaling pathways, and pharmacological antagonists of this process. Approach and Results: We demonstrate that the proinflammatory mediators, IL (interleukin)-1β, TNF (tumor necrosis factor) α, and thrombin, singly and in combination, are potent regulators of capillary tube regression in vitro. These proregressive factors, when added to endothelial cell-pericyte cocultures, led to selective loss of endothelial cell-lined tube networks, with retention and proliferation of pericytes despite the marked destruction of adjacent capillary tubes. Moreover, treatment of macrophages with the TLR (toll-like receptor) agonists Pam3CSK4 and lipopolysaccharide generates conditioned media with marked proregressive activity, that is completely blocked by a combination of neutralizing antibodies directed to IL-1β and TNFα but not to other factors. The same combination of blocking antibodies, as well as the anti-inflammatory cytokine IL-10, interfere with macrophage-dependent hyaloid vasculature regression in mice suggesting that proinflammatory cytokine signaling regulates capillary regression in vivo. In addition, we identified a capillary regression signaling signature in endothelial cells downstream of these proregressive agents that is characterized by increased levels of ICAM-1 (intercellular adhesion molecule-1), phospho-p38, and phospho-MLC2 (myosin light chain-2) and decreased levels of phospho-Pak2, acetylated tubulin, phospho-cofilin, and pro-caspase3. Finally, we identified combinations of pharmacological agents (ie, FIST and FISTSB) that markedly rescue the proregressive activities of IL-1β, TNFα, and thrombin, individually and in combination. CONCLUSIONS:Overall, these new studies demonstrate that the major proinflammatory mediators, IL-1β, TNFα, and thrombin, are key regulators of capillary tube regression-a critical pathological process regulating human disease.
10.1161/ATVBAHA.119.313536
Systematic review and meta-analysis of association of polymorphisms in inflammatory cytokine genes with coronary artery disease.
Tabaei Samira,Motallebnezhad Morteza,Tabaee Seyedeh Samaneh
Inflammation research : official journal of the European Histamine Research Society ... [et al.]
BACKGROUND:It has comprehensively been acknowledged that a genetic contribution, especially in immune inflammatory players, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, are critically involved in the pathophysiology of coronary artery disease (CAD). This meta-analysis study aimed to reach a conclusive understanding of the role of genetic polymorphisms, including IL6 gene C572G (rs1800796) and G174C (rs1800795) as well as TNFA gene G238A (rs361525) and G308A (rs1800629) in susceptibility to CAD. METHODS:Two major databases, namely MEDLINE and Scopus, were searched to find the studies surveying the mentioned polymorphisms and CAD susceptibility up to July 2020. Association comparison between the polymorphisms and CAD susceptibility were assessed using pooled odds ratio (OR) and their corresponding 95% confidence interval (CI). RESULTS:This meta-analysis study was conducted on 69 papers (73 population studies), comprising 5062 patients and 8446 controls for IL6 gene rs1800796 (17 studies), 13801 patients and 16215 controls for IL6 gene rs1800795 (38 studies), 1439 patients and 2850 controls for TNFA gene rs361525 (5 studies), and 5051 patients and 3958 controls for TNFA gene rs1800629 (13 studies), according to inclusion and exclusion criteria. There were statistically positive association between all genetic comparisons of IL6 gene rs1800795 polymorphism and the CAD risk. Moreover, the recessive model (CC vs. CG + GG) in IL6 gene rs1800796 polymorphism had marginally significant association with decreased risk of CAD. None of the TNFA gene polymorphisms were associated with CAD risk. CONCLUSIONS:The meta-analysis revealed the positive association of IL6 gene rs1800795 polymorphism in susceptibility to CAD.
10.1007/s00011-020-01385-3
Docosahexaenoic acid-enriched phospholipids and eicosapentaenoic acid-enriched phospholipids inhibit tumor necrosis factor-alpha-induced lipolysis in 3T3-L1 adipocytes by activating sirtuin 1 pathways.
Yang Yu-Hong,Hao Yi-Ming,Liu Xiao-Fang,Gao Xiang,Wang Bao-Zhen,Takahashi Koretaro,Du Lei
Food & function
Some chronic diseases such as cancer-associated cachexia (CAC) and obesity are associated with the overproduction of tumor necrosis factor-alpha (TNF-α) that stimulates excess lipolysis in adipocytes. Our previous studies have shown that docosahexaenoic acid-enriched phospholipids (DHA-PL) and eicosapentaenoic acid-enriched phospholipids (EPA-PL) ameliorated CAC and obesity-related metabolic disorders. To identify the molecular mechanisms involved, we examined the impact and the associated signaling pathways of DHA-PL and EPA-PL on TNF-α-induced lipolysis in 3T3-L1 adipocytes. The present results revealed that DHA-PL and EPA-PL inhibited the TNF-α-induced increase of glycerol release and protected lipid droplets. In addition, DHA-PL and EPA-PL increased DHA and EPA contents in the phospholipid fraction of adipocytes, respectively. Moreover, DHA-PL and EPA-PL enhanced sirtuin 1 (SIRT1) deacetylase activity and its protein expression. By activating SIRT1, DHA-PL and EPA-PL upregulated the G0/G1 switch gene 2 protein level to inhibit adipose triglyceride lipase activity, activate AMP-activated protein kinase to reverse the downregulation of perilipin expression and phosphorylation of hormone-sensitive lipase (HSL) at Ser565 and prevent the phosphorylation of HSL at Ser660. Furthermore, DHA-PL and EPA-PL improved glucose uptake and glucose transporter type 4 translocation to the plasma membrane in TNF-α-treated adipocytes. Thus, it was concluded that DHA-PL and EPA-PL inhibit TNF-α-induced lipolysis in 3T3-L1 adipocytes by activating the SIRT1 pathways.
10.1039/d1fo00157d
TNF-α: The shape of small molecules to come?
Dömling Alexander,Li Xin
Drug discovery today
In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira® generated US$165.8 billion in cumulative sales and snatched the crown for the industry's most successful drug from Lipitor (atorvastatin). TNF-α is a major component in beneficial and disease-related inflammation and TNF-α-inhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-α inhibitors, such as Alzheimer's disease (AD) or major depression. However, the nature of TNF-α-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.
10.1016/j.drudis.2021.06.018
L-carnitine protects cardiac damage by reducing oxidative stress and inflammatory response via inhibition of tumor necrosis factor-alpha and interleukin-1beta against isoproterenol-induced myocardial infarction.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BRIEF INTRODUCTION:Myocardial infarction (MI) is a common manifestation of certain cardiac diseases where oxidative stress and fibrosis aggravate the condition markedly. MAIN OBJECTIVE OF THE STUDY:Investigation of L-carnitine's cardioprotective roles and mechanism of action in a rat model of MI. METHODS:To develop a MI animal model, Isoproterenol (ISO) was administered in male Long Evans rats where animals were divided into five groups (six rats/group). The oxidative stress and antioxidant enzyme activities were determined by different biochemical tests. The real-time PCR was performed to determine the expression of TNF-α and Il-1β. Histopathological observations by hematoxylin-eosin and Masson trichrome were made to observe the tissue damage and fibrosis in heart and kidney. SIGNIFICANT FINDINGS FROM THE STUDY:The ISO-treated rats showed increased levels of troponin I and lipid peroxidation and lower antioxidant enzyme activity in heart and kidney tissues. The levels of TNF-α and IL-1β were also increased in ISO-rats. Co-administration of L-carnitine with ISO reversed all these parameters. The elevated levels of uric acid and creatinine kinase and ALP, AST and ALT activities in ISO-rats were also significantly reduced by L-carnitine administration. L-carnitine markedly decreased the infiltration of inflammatory cells and improved the tissue architecture in heart and kidney. Control animals did not show any appreciable response upon L-carnitine administration. RELEVANT CONTRIBUTION TO KNOWLEDGE:These results suggest that L-carnitine plays a defensive role against cardiac and renal damage in ISO-treated MI rat model via suppressing oxidative stress and increasing antioxidant enzyme functions through inhibition of TNF-α and IL-1β.
10.1016/j.biopha.2021.112139
The Effect of High-Fat Diet and Exercise Intervention on the TNF-α Level in Rat Spleen.
Feng Lin,Ma Yinan
Frontiers in immunology
High-fat diet (HFD) consumption can trigger chronic inflammation in some tissues. However, it remains unclear if HFD induces chronic inflammation in the spleen. This investigation aims to address the effect of HFD consumption and exercise intervention on the level of tumor necrosis factor alpha (TNF-α) in the spleen. Rats were subjected to HFD feeding and/or moderate-intensity treadmill running. The TNF-α levels in plasma and spleen were detected by ELISA. The mass and total cell numbers of the spleen were measured. In addition, the expression of TNF-α and its relevant gene mRNAs in macrophages from the spleen were analyzed by qRT-PCR. We found that HFD consumption did not significantly affect the mass and total cell numbers of the spleen. However, HFD consumption significantly increased splenic TNF-α level, the expression of TNF-α, toll-like receptor 4, and nuclear factor κB p65 mRNAs. In contrast, the expression of nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) mRNA in macrophages was downregulated. Additionally, exercise abolished the increase in splenic TNF-α level as well as the abnormal expression of TNF-α and related gene mRNAs in macrophages in HFD-fed rats. In conclusion, our results reveal that HFD consumption increases TNF-α level in the spleen, which is along with upregulation of the expression of TLR4 and NF-κB mRNAs as well as downregulation of the expression of α7nAChR mRNA in splenic macrophages in rats. Exercise abolished detrimental effects of HFD on TNF-α level in the spleen and prevented abnormal expression of these genes in the macrophages from rat spleen.
10.3389/fimmu.2021.671167
Protective effects of tanshinone ⅡA on endothelial progenitor cells injured by tumor necrosis factor-α.
Wang Xing-Xiang,Yang Jin-Xiu,Pan Yan-Yun,Zhang Ye-Fei
Molecular medicine reports
Tanshinone ⅡA (Tan ⅡA) is a Traditional Chinese Medicine commonly used in Asian and Western countries for the prevention and treatment of cardiovascular disorders, such as atherosclerosis. Endothelial dysfunction and associated inflammatory processes have a critical role in the development of atherosclerosis. Endothelial progenitor cells (EPCs) have been demonstrated to be involved in certain aspects of the endothelial repair process. The present study aimed to investigate the putative protective effects of Tan ⅡA on EPCs injured by tumor necrosis factor‑α (TNF‑α). The potential effects of Tan ⅡA on TNF-α-stimulated EPC proliferation, migration, adhesion, in vitro tube formation ability and paracrine activity were investigated in the current study. The results indicated that TNF‑α impaired EPC proliferation, migration, adhesion capacity and vasculogenesis ability in vitro as well as promoted EPC secretion of inflammatory cytokines, including monocyte chemoattractant protein‑1 (MCP‑1), interleukin‑6 (IL‑6) and soluble CD40 ligand (sCD40L). However, Tan ⅡA was able to reverse these effects. In conclusion, these findings demonstrated that Tan ⅡA may have the potential to protect EPCs against damage induced by TNF‑α. Therefore, these results may provide evidence for the pharmacological basis of Tan ⅡA and its potential use in the prevention and treatment of early atherosclerosis associated with EPC and endothelial damage.
10.3892/mmr.2015.3969
ERK2 and Akt are negative regulators of insulin and Tumor Necrosis Factor-α stimulated VCAM-1 expression in rat aorta endothelial cells.
Pott Gregory B,Tsurudome Mark,Bamfo Nadia,Goalstone Marc L
Journal of inflammation (London, England)
BACKGROUND:Diabetes is quickly becoming the most widespread disorder in the Western world. Among the most prevalent effects of diabetes is atherosclerosis, which in turn is driven in part by inflammation. Both insulin and Tumor Necrosis Factor-alpha (TNFα) increase the presence of Vascular Cellular Adhesion Molecule-1 (VCAM-1) expression. The aim of this study is to determine the effects of downregulating Extracellular signal-Regulated Kinase-2 (ERK2) and Akt on insulin and TNFa-stimulated VCAM-1 expression. METHODS:Here we begin to define the relationships between ERK2 and Akt regulation of insulin and TNFα-stimulated VCAM-1 expression in Rat Arterial Endothelial Cells (RAEC) by transfecting RAEC with ERK2 and Akt RNA interference (RNAi) and then treating these cells with insulin (10 nM) or TNFα (10 ng/mL) alone or in combination. RESULTS:Western blot analyses, flow cytometry and confocal microscopy were used to determine changes in VCAM-1 expression within the above-stated parameters. Cells transfected with ERK2 or Akt RNAi plasmids increased insulin and TNFα-stimulated VCAM-1 total protein expression significantly (P < 0.05) greater than that seen in mock transfected cells and expressed cell surface VCAM-1 greater than that seen in mock transfected cells as indicated by flow cytometry and confocal microscopy. Nevertheless, the decrease of both kinases did not increase insulin or TNFα-stimulated VCAM-1 expression above that seen when one or the other RNAi was present. CONCLUSIONS:Taken together, our results demonstrate that ERK2 and Akt may be negative regulators of insulin and TNF-α stimulated VCAM-1 and that their loss or down regulation might upregulate VCAM-1 expression and contribute to vascular disease.
10.1186/s12950-016-0115-6
Tumor necrosis factor-α regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosis.
Rao Velidi H,Rai Vikrant,Stoupa Samantha,Subramanian Saravanan,Agrawal Devendra K
Atherosclerosis
OBJECTIVE:To determine the relationship between increased triggering receptor expressed on myeloid cells (TREM)-1 and plaque stability in atherosclerotic carotid stenosis. METHODS:The mRNA transcripts and protein for TREM-1, MMP-1, MMP-9, collagen type I (COL1A1) and collagen type III (COL3A1) were analyzed by qPCR and immunofluorescence in both tissues and VSMCs isolated from atherosclerotic carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. RESULTS:The TREM-1, MMP-1 and MMP-9 mRNA transcripts were significantly increased (TREM-1, p < 0.01; MMP-1, p < 0.01 and MMP-9, p < 0.001) while COL1A1 and COL3A1 mRNA transcripts were decreased (p < 0.001) in VSMCs isolated from carotid plaques of symptomatic (S) than asymptomatic (AS) patients. Stimulation of cells with TNF-α further increased the mRNA transcripts of TREM-1, MMPs, COL1A1 and COL3A1. Modulation of TREM-1 by treatment with TREM-1 decoy receptor rTREM-1/Fc, and either TREM-1 antibodies or TREM-1 siRNA attenuated the TNF-α-induced expression of MMP-1 and MMP-9 (p < 0.01) and COL1A1 and COL3A1 (p < 0.01) in S compared to AS VSMCs isolated from carotid plaques. Inhibition of NF-kB (BAY 11-7085), JNK (SP600125) and PI3K (LY294002) signaling pathways decreased the expression of TREM-1 (p < 0.01), MMP-1 (p < 0.001) and MMP-9 (p < 0.01) in TNF-α-treated VSMCs isolated from S carotid plaques compared to AS patients. CONCLUSION:Increased expression of TREM-1 in S compared to AS patients involving MMP-1 and MMP-9 suggest a potential role of TREM-1 in plaque destabilization. Selective blockade of TREM-1 may contribute to the development of new therapies and promising targets for stabilizing vulnerable atherosclerotic plaques.
10.1016/j.atherosclerosis.2016.03.021
Tumor Necrosis Factor-α and C-C Motif Chemokine Ligand 18 Associate with Atherosclerotic Lipid Accumulation and .
Orekhov Alexander N,Nikiforov Nikita G,Elizova Natalia V,Korobov Gleb A,Aladinskaya Anastasia V,Sobenin Igor A,Bobryshev Yuri V
Current pharmaceutical design
Atherosclerosis is regarded as a chronic inflammatory disease associated with changes in the innate immune system functioning and cytokine disturbances. Local inflammation in the arterial wall is an important component in the development and growth of atherosclerotic plaques. Inside the lesions, both pro- and antiinflammatory cytokines were detected, highlighting the complexity of the atherosclerotic process. However, little is known about the expression of these signaling molecules in early human atherosclerotic lesions. In this study, we explored localization of a pro-inflammatory cytokine, tumor necrosis factor-α (TNFα), and anti-inflammatory chemokine, C-C motif chemokine ligand 18 (CCL18), in the arterial wall of human aorta. We noticed differences in the intensity of staining for TNFα and CCL18 in atherosclerotic lesions and grossly normal areas, as well as differences in their localization. While CCL18 prevailed in the areas close to the aortic lumen, TNFα was localized in deeper layers of the intima. We next studied the expression of TNFα and CCL18 mRNA in lesions corresponding to different stages of atherosclerosis progression and found that it was maximal in lipofibrous plaques that are most enriched in lipids. To test the hypothesis that cytokine expression can be associated with lipid accumulation, we studied the TNFα and CCL18 expression profiles in primary human monocyte-derived macrophages after inducing lipid accumulation by incubating cultured cells with atherogenic LDL. We found that intracellular cholesterol accumulation was associated with upregulation of both TNFα and CCL18, confirming our hypothesis. These results encourage further investigation of cytokine expression in human atherosclerotic lesions and its role in the atherosclerosis progression.
10.2174/1381612824666180911120726
Tumor Necrosis Factor-α Gene Expression in Epicardial Adipose Tissue is Related to Coronary Atherosclerosis Assessed by Computed Tomography.
Kitagawa Toshiro,Yamamoto Hideya,Hattori Takuya,Sentani Kazuhiro,Takahashi Shinya,Senoo Atsuhiro,Kubo Yumiko,Yasui Wataru,Sueda Taijiro,Kihara Yasuki
Journal of atherosclerosis and thrombosis
AIMS:Tumor necrosis factor (TNF)-α reportedly has key pro-inflammatory properties in both atherosclerosis and adipocytes. To further investigate the biologic impact of epicardial adipose tissue (EAT) on coronary atherosclerosis, we evaluated the relationship between TNF-α gene expression in EAT and clinically-assessed coronary atherosclerosis on computed tomography (CT). METHODS:We studied 47 patients before cardiac surgery (coronary artery bypass grafting [CABG], n=26; non-CABG, n=21), assessing visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and the presence of non- and/or partially-calcified coronary plaque (NCP) on CT angiography. EAT and subcutaneous adipose tissue (SAT) samples were obtained during cardiac surgery. TNF-α mRNA in EAT was measured using quantitative real-time PCR, and normalized to that of SAT as control adipose tissue. RESULTS:There was no difference in the TNF-α expression level between patients scheduled for CABG and non-CABG surgery (p=0.23), or among the subgroups based on CCS (p=0.68), while patients with NCP had the higher TNF-α expression level than those without NCP (median [interquartile range], 2.50 [1.01-5.53] versus. 1.03 [0.64-2.16], p=0.022). On multivariate analysis adjusted for age, sex, coronary risk factors, statin therapy, CABG versus non-CABG, VAT area, and EAT volume, the presence of NCP had close correlation with the elevated TNF-α expression level (β=0.79, p=0.003). CONCLUSIONS:TNF-α expressed regionally in EAT may exert potent effects on the progression of coronary atherosclerosis, suggesting a contribution of EAT to coronary artery disease through behavior of molecule.
10.5551/jat.41178
Time and Concentration Dependent Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Induced Endothelial Activation.
Li Meng,van Esch Betty C A M,Henricks Paul A J,Garssen Johan,Folkerts Gert
Frontiers in pharmacology
Endothelial activation is characterized by excessive production of cytokines and chemokines as well as adhesion molecules expression which is involved in the development of atherosclerosis. The aim of our study is to investigate the effects of short chain fatty acids (SCFA) on lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNFα)-induced endothelial activation. Human umbilical vein endothelial cells (HUVEC) were pre-treated with acetate (10 mM), butyrate (0.1 mM) or propionate (0.3 mM) for 1, 16, or 24 h and then stimulated with LPS (1 or 10 μg/ml) or TNFα (100 pg/ml or 1 ng/ml) for 6, 12, or 24 h. Cytokines in the supernatant were measured by ELISA. HUVEC were pre-treated with acetate (10 mM), butyrate (5 mM) or propionate (10 mM) for 24 h and then stimulated with LPS (1 μg/ml) or TNFα (1 ng/ml) for 8 h. The expression of the adhesion molecules intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was detected by flow cytometry. The human blood mononuclear cell adhesive level to HUVEC monolayer was measured. LPS and TNFα induced a significant increase in the release of interleukin-6 (IL-6) and IL-8. Acetate, butyrate and propionate reduced IL-6 and IL-8 levels and the magnitude was dependent on the incubation times. LPS or TNFα increased ICAM-1 and VCAM-1 expression. Pre-incubation with acetate had no effect. In contrast, butyrate and propionate decreased VCAM-1 expression in TNFα stimulated cells but showed no effects on ICAM-1 expression. Butyrate significantly inhibited the adhesion of mononuclear cells to an endothelial monolayer and propionate was less effective. SCFA, including acetate, butyrate and propionate, influenced LPS- or TNFα-induced endothelial activation by inhibiting the production of IL-6 and IL-8, and reducing the expression of VCAM-1 and subsequent cell adhesion. Results were dependent on the concentrations and pre-incubation time of each SCFA and stimulation time of LPS or TNFα.
10.3389/fphar.2018.00233
Tumor Necrosis Factor-alpha Gene Expression in PBMCs of Iranian Azeri Turkish Patients with Premature Coronary Artery Disease (Age .50 Years).
Hassan-Nejhad Mahssa,Bagheri Morteza,Khadem-Vatani Kamal,Seyed Mohammad Zad Mir Hossein,Abdi Rad Isa,Rahimi Behzad,Rostamzadeh Ali,Rahimlou Amir
Maedica
BACKGROUND:Coronary artery disease is the leading cause of disability and mortality in Iran and worldwide. Tumor necrosis factor-alpha is a pro-inflammatory cytokine that plays a key role in inflammatory cascades and atherosclerosis. It regulates cytokine networks and adhesion molecule expression, and activates several signal transduction pathways, being also known as transducer of cardiovascular diseases, especially premature coronary artery disease. OBJECTIVE:The aim of the present study was to investigate tumor necrosis factor-alpha gene expression in Iranian Azeri Turkish patients with premature coronary artery disease (age ≤50 years). MATERIAL AND METHODS:Eighty four individuals (42 cases and 42 controls) were enrolled in the study. Total RNA was extracted from patients with premature coronary artery disease using RNX-Plus Solution (Cat. No.: RN7713C) and reverse transcribed into cDNA. The tumor necrosis factor-alpha mRNA expression level was evaluated using Real-Time PCR. RESULTS:The mean ± SE of fold in cases and controls were 1.1±1.08 and 1.6±3.4, respectively. The mean expression of tumor necrosis factor-alpha mRNA (fold) was not statistically different between the tested groups (P value 0.4). OUTCOMES:Our outcome failed to find evidence for any association between tumor necrosis factor-alpha mRNA expression and premature coronary artery disease. Large scale, more detailed studies are further needed to prove our results and to propose other mechanisms in the pathophysiology of premature coronary artery disease.
Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor α-mediated activation.
Garczorz Wojciech,Gallego-Colon Enrique,Kosowska Agnieszka,Kłych-Ratuszny Agnieszka,Woźniak Michał,Marcol Wiesław,Niesner K J,Francuz Tomasz
Cardiovascular therapeutics
INTRODUCTION:Cardiovascular disease is the main cause of mortality and morbidity in the industrialized world. Incretin-mimetic compounds such as exenatide are currently used in the treatment of type 2 diabetes. AIMS:We investigated the effects of incretin drugs on apoptosis, adhesion molecule expression, and concentration of extracellular matrix (ECM) metalloproteinases under inflammatory conditions within the context of atherosclerotic plaque formation of both human coronary artery endothelial cells (hCAECs) and human aortic endothelial cells (hAoECs). TNF-α-stimulated hCAEC and hAoEC were treated with exenatide (1 and 10 nmol/L) and GLP-1 (10 and 100 nmol/L) then evaluated for caspase 3/7 activity and assayed for protein levels of adhesion molecules sICAM-1, sVCAM-1, and P-selectin. Concentrations of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-9, and their inhibitors-tissue inhibitor of metalloproteinases (TIMPs), TIMP-1, TIMP-2 were also measured to evaluate the effects on extracellular matrix turnover within an inflammatory environment. Intracellular signaling pathways were evaluated via transfection of endothelial cells with a GFP vector under the NF-κB promoter. RESULTS:Our experimental data suggest that GLP-1 receptor (GLP-1R) agonists downregulate activation of NF-κB and adhesion molecules ICAM and VCAM, but not P-selectin, in both endothelial cell lines. Exendin-4 and GLP-1 modulate the expression of MMPs and TIMPs, with statistically significant effects observed at high concentrations of both incretins. Expressive modulation may be mediated by NF-κB as observed by activation of the vector when stimulated under inflammatory conditions. CONCLUSION:These findings indicate that GLP-1 analogs have anti-inflammatory properties in endothelial cells that may play an important role in preventing atherosclerosis.
10.1111/1755-5922.12317
Autophagy mediates tumor necrosis factor-α-induced phenotype switching in vascular smooth muscle A7r5 cell line.
García-Miguel Marina,Riquelme Jaime A,Norambuena-Soto Ignacio,Morales Pablo E,Sanhueza-Olivares Fernanda,Nuñez-Soto Constanza,Mondaca-Ruff David,Cancino-Arenas Nicole,San Martín Alejandra,Chiong Mario
PloS one
Vascular smooth muscle cells (VSMC) dedifferentiation from a contractile to a synthetic phenotype contributes to atherosclerosis. Atherosclerotic tissue has a chronic inflammatory component with high levels of tumor necrosis factor-α (TNF-α). VSMC of atheromatous plaques have increased autophagy, a mechanism responsible for protein and intracellular organelle degradation. The aim of this study was to evaluate whether TNF-α induces phenotype switching of VSMCs and whether this effect depends on autophagy. Rat aortic Vascular smooth A7r5 cell line was used as a model to examine the phenotype switching and autophagy. These cells were stimulated with TNF-α 100 ng/mL. Autophagy was determined by measuring LC3-II and p62 protein levels. Autophagy was inhibited using chloroquine and siRNA Beclin1. Cell dedifferentiation was evaluated by measuring the expression of contractile proteins α-SMA and SM22, extracellular matrix protein osteopontin and type I collagen levels. Cell proliferation was measured by [3H]-thymidine incorporation and MTT assay, and migration was evaluated by wound healing and transwell assays. Expression of IL-1β, IL-6 and IL-10 was assessed by ELISA. TNF-α induced autophagy as determined by increased LC3-II (1.91±0.21, p<0.001) and decreased p62 (0.86±0.02, p<0.05) when compared to control. Additionally, TNF-α decreased α-SMA (0.74±0.12, p<0.05) and SM22 (0.54±0.01, p<0.01) protein levels. Consequently, TNF-α induced migration (1.25±0.05, p<0.05), proliferation (2.33±0.24, p<0.05), and the secretion of IL-6 (258±53, p<0.01), type I collagen (3.09±0.85, p<0.01) and osteopontin (2.32±0.46, p<0.01). Inhibition of autophagy prevented all the TNF-α-induced phenotypic changes. TNF-α induces phenotype switching in A7r5 cell line by a mechanism that required autophagy. Therefore, autophagy may be a potential therapeutic target for the treatment of atherosclerosis.
10.1371/journal.pone.0197210
Differences in carotid atherosclerosis between patients with ankylosing spondylitis treated with tumor necrosis factor-α antagonists and healthy matched controls.
Zardi Enrico Maria,Pipita Maria Elena,Giorgi Chiara,Lichinchi Domenico,Zardi Domenico Maria,Afeltra Antonella
Medicine
An increased vascular risk is present in patients with ankylosing spondylitis (AS). In this report, we evaluate the presence and grade of atherosclerosis in patients with AS, uninterruptedly treated with tumor necrosis factor-α (TNF-α) antagonists for 2 years, in comparison to that in a nontreated group of healthy controls.Fourteen patients with AS and 14 healthy controls underwent carotid sonography to measure intima-media thickness (IMT) and to evaluate the presence of plaque. Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index scores, erythrocyte sedimentation rate, C-reactive protein, glycemia, total cholesterol, and triglyceride levels were also recorded.Patients with AS showed significantly lower values of mean and maximum IMT at the level of the common carotid (P = .02 and .04, respectively) and the carotid bulb (P = .0006 and .0005, respectively) compared to those of healthy controls. They also had a number of carotid plaques significantly lower than that of healthy controls (P = .02). No differences were found in IMT values at the level of internal carotid between the 2 populations.The significantly lower carotid atherosclerosis found in patients with AS treated with TNF antagonists than in healthy controls shows the important complementary role of this treatment in reducing vascular disease progression probably by decreasing inflammation.
10.1097/MD.0000000000011250
Hyperoside suppresses tumor necrosis factor α-mediated vascular inflammatory responses by downregulating mitogen-activated protein kinases and nuclear factor-κB signaling.
Jang Seon-A,Park Dae Won,Sohn Eun Hwa,Lee Sung Ryul,Kang Se Chan
Chemico-biological interactions
Vascular inflammation has been suggested to play a key role in the initiation and progression of atherosclerosis. Hyperoside (HPS) is a plant-derived quercetin 3-d-galactoside reported to have anti-inflammatory, anti-oxidant, anti-cancer, anti-hyperglycemic, anti-coagulant, and cardioprotective activities. However, the effects of HPS on vascular inflammation have not been studied. Therefore, in this study, we investigated the suppressive effect of HPS on tumor necrosis factor-α (TNFα)-dependent inflammatory responses in MOVAS-1 cells, a murine vascular smooth muscle cell (VSMC) line. HPS did not show any significant cytotoxicity up to 10 μg/mL over 24 h. TNFα challenge of VSMCs significantly increased the mRNA (3-fold) and protein expression (20-fold) of vascular cell adhesion molecule-1 (VCAM-1). However, these increases were abolished in the presence of HPS. Additionally, HPS significantly decreased monocyte adhesion to TNFα-stimulated VSMCs in a dose-dependent manner. Further, TNFα challenge induced activation of mitogen-activated protein kinases (MAPKs), such as p38 MAPK (38.0 ± 3.08 fold), JNK (51.6 ± 2.26 fold), and ERK (14.1 ± 0.77 fold); expression of nuclear factor-κB (NF-κB; ≅ 4-fold) and TNF receptor 1 (TNFR1; 2.7 ± 0.198 fold) were also increased. Notably, the TNFα-induced expression of these molecules was also significantly inhibited by the presence of HPS. Given that p38 MAPK, JNK, ERK, NF-κB, and TNFR1 all play regulatory roles in the expression of VCAM-1, this study provides insight into the mechanism of action of HPS. In summary, HPS can inhibit TNFα-mediated vascular inflammatory responses and has potential as a new anti-atherosclerotic drug.
10.1016/j.cbi.2018.08.013
Anti-tumor necrosis factor-α therapy increases plaque burden in a mouse model of experimental atherosclerosis.
Oberoi Raghav,Vlacil Ann-Kathrin,Schuett Jutta,Schösser Florian,Schuett Harald,Tietge Uwe J F,Schieffer Bernhard,Grote Karsten
Atherosclerosis
BACKGROUND AND AIMS:Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-α. Genetic disruption of Tnf-α reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-α blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-α inhibition on plaque development in experimental atherosclerosis. RESULTS:10 week old male Ldlr mice were divided into 4 groups (n = 7-10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-α monoclonal antibody CNTO5048 (CNT) or a control IgG was administered. RESULTS:CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-α inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-α inhibitor treatment. CONCLUSIONS:Although up to 12-week pharmacological inhibition of TNF-α in Ldlr mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile.
10.1016/j.atherosclerosis.2018.08.030
Salidroside prevents tumor necrosis factor-α-induced vascular inflammation by blocking mitogen-activated protein kinase and NF-κB signaling activation.
Li Ruoshui,Dong Zhen,Zhuang Xinyu,Liu Rongchen,Yan Fangying,Chen Yufei,Gao Xiufang,Shi Haiming
Experimental and therapeutic medicine
Vascular inflammation is a key factor in the pathogenesis of atherosclerosis. Salidroside is an important active ingredient extracted from the root of the plant, which has been reported to have antioxidative, anti-cancer, neuroprotective and cardioprotective effects. However, the effects of salidroside on vascular inflammation have not been clarified. The purpose of the present study was to investigate the protective effects of salidroside against tumor necrosis factor (TNF)-α-induced vascular inflammation in cardiac microvascular endothelial cells (CMECs), a specific cell type derived from coronary micro-vessels. Over a 24-h period, salidroside did not exert any significant cytotoxicity up to a dose of 100 µM. Additionally, salidroside decreased the expression levels of the cell adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in TNF-α-stimulated CMECs, thus suppressing monocyte-to-CMEC adhesion. Salidroside also decreased the production of inflammatory cytokines such as interleukin (IL)-1β, IL-6 and monocyte chemotactic protein 1 (MCP-1) in TNF-α-induced CMECs, as well as suppressing TNF-α-activated mitogen-activated protein kinase (MAPK) and NF-κB activation. Since MAPKs and NF-κB both serve notable roles in regulating the expression of VCAM-1, IL-1β, IL-6 and MCP-1, the present study provided a preliminary understanding of the mechanism underlying the protective effects of salidroside. Overall, salidroside alleviated vascular inflammation by mediating MAPK and NF-κB activation in TNF-α-induced CMECs. These results indicated that salidroside may have potential applications as a therapeutic agent against vascular inflammation and atherosclerosis.
10.3892/etm.2019.8064
The impacts of C1q/TNF-related protein-15 and adiponectin on Interleukin-6 and tumor necrosis factor-α in primary macrophages of patients with coronary artery diseases.
Ahmadi Reza,Fadaei Reza,Shokoohi Nahrkhalaji Abolfazl,Panahi Ghodratollah,Fallah Soudabeh
Cytokine
Atherosclerosis is a progressive inflammatory disease characterized by the accumulation of lipids in the arterial wall. Inflammation plays a key role in the pathogenesis of atherosclerosis and some previous studies have shown the role of adipokines during the inflammatory process of atherosclerosis. Therefore, the present study aimed to evaluate the impacts of adiponectin and CTRP15 on inflammatory cytokines secretions from THP1 and primary macrophages. METHODS:THP1 monocytes were differentiated to macrophages and primary monocytes were then isolated from patients with coronary artery disease and controls who were differentiated to macrophages. Macrophages were treated with LPS, LPS+adiponectin, and LPS+CTRP15. RESULTS:Adiponectin and CTRP15 have reduced IL-6 and TNF-α secretions from LPS-induced THP1 macrophages, and the CTRP15 indicated a more potent anti-inflammatory property compared to adiponectin. In addition, adiponectin reduced cytokines' expressions and secretions in primary macrophages of both patient and control groups. However, CTRP15 has only reduced cytokines' expressions and secretions in controls and it was not able to ameliorate inflammation in macrophages of CAD patients. CONCLUSION:The results of the present study indicate anti-inflammatory impact of adiponectin and CTRP15, while this property was stronger for CTRP15. In addition, it seems likely that anti-inflammatory CTRP15's impact on macrophages in the CAD patients was weaker than macrophages from the controls.
10.1016/j.cyto.2021.155470
Tumor Necrosis Factor-Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis: A Systematic Review.
Cureus
Rheumatoid arthritis (RA) is an autoimmune disease that, if untreated or poorly controlled, can cause significant morbidity in terms of loss of physical function and higher mortality due to higher cardiovascular risk. The standard of care for this disease is the use of disease-modifying antirheumatic drugs (DMARDs). However, patients unable to reach low disease activity or remission and patients unable to tolerate conventional DMARDs will be switched to biologic therapy, a subset of which includes anti-tumor necrosis factor-alpha inhibitors. Since tumor necrosis factor-alpha inhibitors (TNFi) inhibit the inflammatory cascade, they also play an essential role in dampening the progression of atherosclerosis and altering the risk of cardiovascular outcomes in RA. In this study, we assessed the risk of cardiovascular diseases, namely, congestive heart failure, nonfatal myocardial infarction, cerebrovascular disease, and coronary artery disease. We carried out the analysis by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and conducted a literature search utilizing the following databases: PubMed, Science Direct, and Cochrane Library. Using the search strategy, we found a total of 19 articles that fit the inclusion and exclusion criteria, in addition to passing the risk of bias assessment. This is composed of three systematic reviews with meta-analyses, three randomized control studies, four narrative reviews, and nine cohort studies. In this systematic review, it was found that treatment with TNFi causes a corresponding reduction in the risk of cardiovascular events. This review encourages further dissection into the inner workings of TNFi in reducing the risk of cardiovascular disease among patients with RA.
10.7759/cureus.26430
Abdominal aortic calcification in patients with inflammatory bowel disease: does anti-tumor necrosis factor α use protect from chronic inflammation-induced atherosclerosis?
Intestinal research
BACKGROUND/AIMS:Abdominal aortic calcium (AAC) deposition has been suggested as a marker of early atherosclerosis. There is no published data on the evaluation of AAC in inflammatory bowel disease (IBD). METHODS:AAC was quantified by computed tomography or enterography scans performed in 98 IBD patients and 1:1 age and sex matched controls. AAC deposition was correlated with IBD characteristics, disease activity or severity parameters, laboratory tests and cardiovascular disease (CVD) risk factors. RESULTS:Moderate-severe grade of AAC was found in 35.7% of IBD patients compared to 30.6% of controls (P= 0.544). IBD with CVD and ulcerative colitis patients had significantly higher rates of more severe atherosclerotic lesions (P= 0.001 and P= 0.01, respectively). AAC deposition was similarly distributed in age groups ( < 45, 45-64, and ≥ 65 years) among patients and controls. Multivariate analysis after excluding CVD risk confounders for non-CVD patients found extensive disease (P= 0.019) and lifetime steroids (P= 0.04) as independent risk factors for AAC. Anti-tumor necrosis factor α (TNF-α) use was negatively associated with AAC deposition in non-CVD IBD patients (odds ratio, 0.023; 95% confidence interval, 0.001-0.594; P= 0.023). CONCLUSIONS:More than one-third of IBD patients have moderate to severe AAC. Better control of inflammation with anti-TNF-α agents seems to protect IBD patients from ACC deposition and subsequent atherosclerosis.
10.5217/ir.2022.00017
Cordycepin inhibits vascular adhesion molecule expression in TNF-α-stimulated vascular muscle cells.
Yan Li-Jie,Yang Hai-Tao,Duan Hong-Yan,Wu Jin-Tao,Qian Peng,Fan Xian-Wei,Wang Shanling
Experimental and therapeutic medicine
Atherosclerosis is a chronic inflammatory disease, which is associated with the increased expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Cordycepin is one of the major bioactive components of that has been demonstrated to exert anti-atherogenic activity; however, its molecular mechanisms are poorly understood. The aim of the present study was to examine the effects of cordycepin on the tumor necrosis factor (TNF)-α-induced suppression of adhesion molecule expression. The results of the present study demonstrated that cordycepin markedly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in TNF-α-stimulated human aortic vascular smooth muscle cells (HA-VSMCs). Cordycepin significantly inhibited the TNF-α-induced mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) activation (P<0.05), markedly inhibited the TNF-α-induced expression level of nuclear factor (NF)-κB p65 and markedly prevented the TNF-α-associated degradation of IκBα in HA-VSMCs. The results of the present study suggest that cordycepin inhibits the expression of VCAM-1 and ICAM-1 in TNF-α-stimulated HA-VSMCs via downregulating the MAPK/Akt/NF-κB signaling pathway. Therefore, cordycepin may have a potential therapeutic application for preventing the advancement of atherosclerotic lesions.
10.3892/etm.2017.4746
There is no association between TNF-α gene polymorphisms and the risk of coronary artery heart disease: a meta-analysis.
Huangfu Fengtian,Zhao Xin,Wang Xin,Tang Longqian,Jiang Jie
The Journal of cardiovascular surgery
INTRODUCTION:Coronary artery heart disease (CAD) is a group of complex diseases, including coronary atherosclerosis, myocardial infarction and sudden cardiac death. CAD is also widely accepted as a chronic inflammatory disease. Studies show that pro-inflammatory tumor necrosis factor-alpha (TNF-α) is involved in the CAD pathological pathway and is a reliable predictor of cardiovascular disease. However, the association between TNF-α polymorphisms and CAD risk is still unclear. In this meta-analysis, we investigated the relationship between TNF-α polymorphisms and CAD risk. EVIDENCE ACQUISITION:From EMBASE, Web of science, EBSCO, PubMed and Chinese National Knowledge Infrastructure (CNKI) databases 7525 articles were selected in our study. A meta-analysis on the associations between the T-1031C, C-857T and C-863A polymorphisms and CAD risk was carried out by comparing five genetic models. EVIDENCE SYNTHESIS:In this systematic review 14 studies from six English articles and 1 Chinese article were analyzed. The pooled population included 16,774 subjects (8351 cases and 8423 controls). Our results showed that three polymorphisms (T-1031C, C-857T and C-863A) have no association with CAD risk. CONCLUSIONS:Our results indicated that T-1031C, C-857T and C-863A polymorphisms are not associated with CAD risk.
10.23736/S0021-9509.16.09352-6
Danshenol A inhibits TNF-α-induced expression of intercellular adhesion molecule-1 (ICAM-1) mediated by NOX4 in endothelial cells.
Zhao Wenwen,Feng Haitao,Guo Shuhui,Han Yantao,Chen Xiuping
Scientific reports
ICAM-1 overexpression and subsequent adhesion of leukocytes to endothelial cells play critical roles in the early stage of atherosclerosis. Danshenol A (DA) is an abietane-type diterpenoid isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. The mechanisms under its regulation of adhesion of molecular expression are explored. Here, the effect of DA on TNF-α-induced ICAM-1 expression was investigated in endothelial cells. TNF-α-induced ICAM-1 expression and subsequent adhesion of monocytes, as well as elevated reactive oxygen species (ROS) generation and NOX4 expression were all significantly reversed by DA, siNOX4 and NOX4 inhibitor GKT137831. Furthermore, TNF-α-induced ICAM-1 expression, which was increased via IKKβ/IκBα-mediated activation of NF-κB p65, was also inhibited by DA. Interestingly, NOX4 overexpression suppressed the ICAM-1 expression, and this finding may be ascribed to the activation of Nrf-2. Additionally, NF-κB inhibitor PDTC, siNOX4, or DA can decrease the TNF-α-induced ICAM-1 expression and suppress the adhesion of monocytes. In all, DA inhibited TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion to endothelial cells through the NOX4-dependent IKKβ/NF-κB pathway. Besides, NOX4 played dual role in regulating ICAM-1 expression via diverse signal pathway. This novel bioactivity will make DA a good candidate to be further explored for therapeutic or preventive application for atherosclerosis.
10.1038/s41598-017-13072-1
Quinic acid inhibits vascular inflammation in TNF-α-stimulated vascular smooth muscle cells.
Jang Seon-A,Park Dae Won,Kwon Jeong Eun,Song Hae Seong,Park Bongkyun,Jeon Hyelin,Sohn Eun-Hwa,Koo Hyun Jung,Kang Se Chan
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Atherosclerosis is a chronic inflammatory disease, and the increased expression of adhesion molecules on vascular smooth muscle cells contributes to the progression of vascular disease. Quinic acid (QA) has been shown to possess radioprotection, anti-neuroinflammatory, and anti-oxidant activities; however, an anti-vascular inflammatory effect has not been reported. This study investigated the effect of QA on the expression of vascular cell adhesion molecule-1 (VCAM-1) stimulated by TNF-α in MOVAS cells. Pre-incubation of MOVAS cells, the mouse vascular smooth muscle cell line for 2h with QA (0.1, 1 and 10 μg/mL) dose-dependently inhibits TNF-α-induced mRNA and protein expression of VCAM-1 and monocyte adhesion. QA inhibits TNF-α-stimulated phosphorylation of MAP kinase and NK-κB activation. Our results indicate that QA inhibits the TNF-α-stimulated induction of VCAM-1 in VSMC by inhibiting the MAP kinase and NF-κB signaling pathways and the adhesion capacity of VSMC, which may explain the ability of QA to inhibit vascular inflammation such as atherosclerosis.
10.1016/j.biopha.2017.10.021
Aspirin suppresses TNF-α-induced MMP-9 expression via NF-κB and MAPK signaling pathways in RAW264.7 cells.
Zhang Ping,Wu Chao,Huang Xiao-Hui,Shen Chen-Lin,Li Lin,Zhang Wei,Yao Cheng-Zeng
Experimental and therapeutic medicine
Numerous studies have indicated that the expression of matrix metalloproteinase-9 (MMP-9) contributes to the atherosclerotic plaque hemorrhage and rupture. Aspirin, a non-steroidal anti-inflammation drug, has been known for its anti-platelet effect in the prevention of the vascular complications of atherosclerosis. The present study aimed to investigate the pharmacological effects of aspirin on tumor necrosis factor-α (TNF-α)-induced MMP-9 expression and the underlying molecular mechanisms in murine macrophage RAW264.7 cells. Western blot analysis indicated that the protein level of MMP-9 was reduced by aspirin in a dose-dependent manner. In addition, downregulation of MMP-9 mRNA and activity were detected in aspirin-treated cells using quantitative polymerase chain reaction and a gelatin zymography assay separately. It was also observed that aspirin has a suppressive effect on the activation of nuclear factor (NF)-κB and inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases 1/2, p38 and c-Jun N-terminal kinase. Furthermore, subsequent to inhibition of the MAPK pathway by specific inhibitors (PD98059, SB203580 and SP600125), the expression of MMP-9 was reduced, indicating that the inhibitory effect of aspirin on MMP-9 in TNF-α-treated RAW264.7 cells may be, at least in part, through suppression of NF-κB activation and the MAPK pathway. These findings support the notion that aspirin has therapeutic potential application in the prevention and treatment of atherosclerosis disease.
10.3892/etm.2017.5252
Simvastatin Modulates Interaction Between Vascular Smooth Muscle Cell/Macrophage and TNF-α-Activated Endothelial Cell.
Chu Fujiang,Wang Min,Ma Hongyan,Zhu Jiayong
Journal of cardiovascular pharmacology
Cellular interactions between endothelial cell (EC) and vascular smooth muscle cell (VSMC)/macrophages seem to be greatly changed under inflammatory conditions. Although simvastatin could regulate inflammatory transcription factors in EC and VSMC and also could inhibit leukocyte-endothelium interaction, whether it could modulate VSMC/macrophage functions that are induced by tumor necrosis factor-α (TNF-α)-activated EC remained unclear. The purpose of this study was to investigate the effects of simvastatin on VSMC/macrophage functions, which are induced by TNF-α-activated EC in coculture system in vitro. The results showed that under noncontacting conditions, simvastatin could reduce the proliferation, apoptosis, and TNF-α, IL-6, and vascular endothelial growth factor secretion both in VSMC and macrophage, which is induced by TNF-α-activated EC. And a hypothesis that simvastatin regulates the interactions and the soluble factors between EC and VSMC/macrophages could be drawn. And that might be a potential anti-atherosclerosis mechanism of simvastatin.
10.1097/FJC.0000000000000567
Downregulation of GATA6 in mTOR-inhibited human aortic endothelial cells: effects on TNF-α-induced VCAM-1 expression and monocytic cell adhesion.
American journal of physiology. Heart and circulatory physiology
Increased expression of vascular cell adhesion molecule 1 (VCAM-1) on the aortic endothelium is an early marker of atherogenesis, promoted in part by elevated levels of inflammatory cytokines such as TNF-α. Mammalian target of rapamycin (mTOR) is a ubiquitous signaling molecule that has been considered to contribute to diverse cellular processes through mTOR complex 1 (mTORC1) or complex 2 (mTORC2). This study aimed to elucidate the role of mTOR signaling in TNF-α-induced VCAM-1 expression by the arterial endothelium. Primary human aortic endothelial cells (HAECs) were treated with low-dose (0.1 ng/ml) TNF-α, and VCAM-1 expression was measured by real-time quantitative PCR, Western blot analysis, and flow cytometry. Inhibition of mTOR through siRNA-mediated depletion or treatment with chemical inhibitors rapamycin or torin 1 suppressed VCAM1 transcription, which translated to inhibition of VCAM-1 surface expression by HAECs and concomitant decreased adhesion of monocytes. A promoter luciferase assay and chromatin immunoprecipitation indicated that mTOR regulated VCAM1 transcription through a mechanism involving transcription factor GATA6. Activation of PKC-α and an increase in miR-200a-3p expression, caused by mTOR inhibition but not disruption of mTORC1 or mTORC2 singly or together, decreased TNF-α-induced GATA6 expression and its enrichment at the VCAM1 promoter. In conclusion, mTOR inhibition activates PKC-α independently of disruption of mTORC1 and/or mTORC2, which challenges the conventional wisdom regarding mTOR signaling. Moreover, mTOR signals through transcriptional and posttranscriptional mechanisms to elicit maximal cytokine-induced endothelial inflammation that precedes atherosclerosis. NEW & NOTEWORTHY Both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 contribute to PKC-α activation in the human aortic endothelium. Inhibition of mTOR is not equivalent to disruption of mTORC1 and/or mTORC2 in affecting human aortic endothelial cell signaling. Specifically, inhibition of mTOR causes PKC-α activation and miR-200a-3p upregulation, which independently suppresses TNF-α-induced transcription factor GATA6 expression and subsequently inhibits VCAM-1 expression and monocytic cell adhesion onto the aortic endothelium.
10.1152/ajpheart.00411.2018
Aronia berry extract inhibits TNF-α-induced vascular endothelial inflammation through the regulation of STAT3.
Food & nutrition research
BACKGROUND:Inflammation in endothelial cells induces production of inflammatory cytokines and monocytes adhesion, which are crucial events in the initiation of atherosclerosis. Aronia berry (), also called black chokeberry, contains abundant anthocyanins that have received considerable interest for their possible relations to vascular health. OBJECTIVE:The aim of this study was to investigate whether an anthocyanin-rich extract obtained from aronia berry can attenuate inflammatory responses in vascular endothelial cells. METHODS:As a model of vascular endothelial inflammation, human umbilical vein endothelial cells (HUVECs) pretreated with aronia berry extract were stimulated with tumor necrosis factor-alpha (TNF-α). The expression levels of cytokines and adhesion molecules were analyzed. To investigate the effects of aronia berry extract on the adhesion of THP-1 monocytic cell, the static adhesion assay was carried out. The possible molecular mechanisms by which aronia berry extract regulated vascular inflammatory responses were explored. RESULTS:The mRNA expressions of interleukins (IL-1β, IL-6, and IL-8) and monocyte chemoattractant protein-1 (MCP-1) upregulated by TNF-α were significantly suppressed by pretreatment with aronia berry extract. Aronia berry extract decreased TNF-α-induced monocyte/endothelial adhesion and suppressed vascular cell adhesion molecule-1 (VCAM-1) expression, but did not affect intercellular adhesion molecule-1 (ICAM-1) expression. Moreover, aronia berry extract decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the nuclear levels of STAT3 and interferon regulatory transcription factor-1 (IRF1). The nuclear translocation of nuclear factor-kappa B (NF-κB) was not inhibited by aronia berry extract. CONCLUSION:Aronia berry extract could exert anti-atherosclerotic effects on TNF-α-induced inflammation through inhibition of STAT3/IRF1 pathway in vascular endothelial cells.
10.29219/fnr.v63.3361
Interplay of TNF-α, soluble TNF receptors and oxidative stress in coronary chronic total occlusion of the oldest patients with coronary heart disease.
Li Xia,Zhang Fenglin,Zhou Hualan,Hu Youdong,Guo Dianxuan,Fang Xiang,Chen Ying
Cytokine
BACKGROUND:The interplay of tumour necrosis factor-α (TNF-α) and oxidative stress was related to severities of coronary atherosclerosis and congestive heart failure. We tried to identify TNF-α, soluble tumour necrosis factor-α receptor-1 (sTNFR-1), soluble tumour necrosis factor-α receptor-2 (sTNFR-2) and oxidative stress as potential non-invasive diagnostic and therapeutic biomarkers for coronary chronic total occlusion (CCTO) in the oldest patients with coronary heart disease (CHD). METHODS:We determined the expression levels of TNF-α, sTNFR-1, sTNFR-2, oxidative stress biomarkers (malondialdehyde [MDA], aldosterone [ALD], angiotensin II [Ang II], and high sensitivity C-reactive protein [hs-CRP]) in oldest patients with CCTO. RESULTS:The levels of TNF-α, sTNFR-1, sTNFR-2, MDA, ALD, Ang II and hs-CRP were increased in oldest patients with CCTO (P < 0.001). The CCTO of oldest patients with CHD may involve the interplay of TNF-α, sTNFR-1, sTNFR-2 and oxidative stress. CONCLUSIONS:The TNF-α, sTNFR-1, sTNFR-2 and oxidative stress could be considered as potential non-invasive diagnostic and therapeutic biomarkers for CCTO in the oldest patients with CHD.
10.1016/j.cyto.2019.154836
Effects of 1-year anti-TNF-α therapy on vascular function in rheumatoid arthritis and ankylosing spondylitis.
Végh Edit,Kerekes György,Pusztai Anita,Hamar Attila,Szamosi Szilvia,Váncsa Andrea,Bodoki Levente,Pogácsás Lilla,Balázs Fruzsina,Hodosi Katalin,Domján Andrea,Szántó Sándor,Nagy Zoltán,Szekanecz Zoltán,Szűcs Gabriella
Rheumatology international
Accelerated atherosclerosis, increased cardiovascular morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Vascular function, clinical and laboratory markers and the effects of anti-TNF therapy were assessed in arthritides. Fifty-three 53 patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. A significant improvement of brachial artery FMD was observed after 6 months (p = 0.004). A tendency of FMD improvement was also observed after 12 months (p = 0.065). ccIMT did not change throughout the year. PWV significantly improved after 12 months (p = 0.034). Higher baseline ccIMT (p = 0.009) and PWV (p = 0.038) were associated with clinical non-response (cNR) versus response (cR) to biologics. Multiple analysis confirmed the association of baseline ccIMT with age (p = 0.003) and cNR (p = 0.009), as well as that of baseline PWV with age at diagnosis (p = 0.022) and current chest pain (p = 0.004). Treatment itself determined the 12-month changes in FMD (p = 0.020) and PWV (p = 0.007). In a mixed cohort of RA and AS patients, TNF inhibition improved or stabilized vascular pathophysiology. Inflammation may be associated with FMD, while, among others, cNR may influence vascular function.
10.1007/s00296-019-04497-0
Laquinimod Protects Against TNF-α-Induced Attachment of Monocytes to Human Aortic Endothelial Cells (HAECs) by Increasing the Expression of KLF2.
Drug design, development and therapy
INTRODUCTION:As a worldwide health issue, the treatment and prevention of atherosclerosis present an important goal. Increased levels of proinflammatory cytokines such as TNF-α-associated chronic inflammatory response cause endothelial cells to lose their ability to regulate vascular function. Lipid-laden immune cells are recruited to the endothelium where they adhere to the endothelial wall and invade the intimal space, thereby leading to the development of atherosclerotic lesions, fatty plaques, and thickening of the arterial wall. In the present study, for the first time, we investigated the effects of laquinimod, an immunomodulatory agent used for the treatment of multiple sclerosis, on human aortic endothelial in a TNF-α-induced atherosclerotic microenvironment. At present, the mechanism of action of laquinimod is not well defined. METHODS:The effects of laquinimod on the gene expression of IL-6, MCP-1, VCAM-1, E-selectin, and KLF2 were measured by real-time PCR. ELISA assay was used to determine protein secretion and expression. Phosphorylation of ERK5 and the protein level of KLF2 were measured by Western blot analysis. The attachment of monocytes to endothelial cells was assayed by calcein-AM staining and fluorescent microscopy. RESULTS:Our findings demonstrate that laquinimod reduced the expression of key inflammatory cytokines and chemokines, including IL-6, MCP-1, and HMGB1. We further demonstrate that laquinimod significantly reduced the attachment of monocytes to endothelial cells, which is mediated through reduced expression of the cellular adhesion molecules VCAM-1 and E-selectin. Here, we found that laquinimod could significantly increase the expression of KLF2 through activation of ERK5 signaling. The results of our KLF2 knockdown experiment confirm that the effects of laquinimod observed in vitro are dependent on KLF2 expression. CONCLUSION:Together, these findings suggest a potential antiatherosclerotic capacity of laquinimod. Further research will elucidate the underlying mechanisms.
10.2147/DDDT.S243666
Butyrate mitigates TNF-α-induced attachment of monocytes to endothelial cells.
Wang Yan,Xu Yuanyuan,Yang Mao,Zhang Mingyu,Xiao Mochao,Li Xueqi
Journal of bioenergetics and biomembranes
A major cause of late-life health complications is the cardiovascular disease known as atherosclerosis. The process of atherogenesis is marked by endothelial cell dysfunction, the development of atherogenic lesions, and plaque buildup on the intima of the arterial endothelium. This process is fueled primarily by the adhesion of monocytes to endothelial cells via the actions of the cellular adhesion molecules VCAM-1 and E-selectin. When expressed at their basal levels, these molecules are vital to various cellular processes, but when in a state of overproduction, they drive the progression of atherosclerosis by recruiting monocytes to roll along and adhere to the endothelium. TNF-α is theorized to play a causal role in the development of atherosclerosis, but the exact mechanism remains poorly understood. This cytokine is known to upregulate various factors associated with inflammation and oxidative stress, both of which greatly contribute to endothelial dysfunction and atherogenesis. In the present study, we aimed to elucidate the effect of butyrate on these atherogenic processes. Previously not known to have atheroprotective effects, this natural compound shows promise as a treatment for atherosclerosis. In the present study, we found butyrate to exert various anti-inflammatory and downstream regulatory effects. Namely, butyrate ameliorated the overproduction of adhesion molecules, including VCAM-1 and E-selectin, reduced oxidative stress by reducing the levels of ROS and 4-HNE, and suppressed inflammation via inhibition of MCP-1 and IL-8. Additionally, butyrate rescued the reduced expression of the protective factor KLF2, which was mediated through the ERK5 pathway. Thus, butyrate may serve as a promising treatment against atherosclerosis.
10.1007/s10863-020-09841-9
Biological and Clinical Implications of TNF-α Promoter and CYP1B1 Gene Variations in Coronary Artery Disease Susceptibility.
Cardiovascular & hematological disorders drug targets
BACKGROUND:Cardiovascular diseases (CVD) are important causes of death worldwide. Atherosclerosis is a chronic inflammatory disorder. It is the major cause of CVD and is manifested by ischemic heart disease or coronary artery disease (CAD). TNF-α is a pro-inflammatory cytokine that regulates immune response and promotes the development of atherosclerosis. Cytochrome p450 1B1 (CYP1B1) is an enzyme involved in the metabolism of endogenous and exogenous substrates. OBJECTIVES:This study aimed at examining the association of TNF-α rs1800629 G>A and CYP1B1 rs1056827 G>T gene polymorphisms with CAD susceptibility in an Indian cohort. METHODS:AS-PCR and direct DNA sequencing were used to examine the association of TNF-α rs1800629 G >A and CYP1B1 rs1056827 G>T gene polymorphism with CAD in an Indian cohort. A total of 100 clinically confirmed cases of CAD and 110 matched apparently healthy controls were genotyped. RESULTS:Allelic and genotypic frequencies did not deviate from Hardy-Weinberg equilibrium in the controls (p>0.05) for TNF-α G-308A and CYP1B1 rs1056827G>A. There was no significant difference between the TNF-α rs1800629 A>G genotype distribution between cases and controls (P-value >0.05). A significant difference was observed between the CYP1B1 rs1056827 G>T genotype distribution between CAD cases and controls (p<0.0003). Our result indicated that in the codominant model, the GA genotype of the CYP1B1 rs1056827 G>T was associated with CAD with OR= 2.21(1.17 to 4.15), RR=1.38(1.07 to 1.78), and p<0.013. In the dominant model, the (GA+AA) genotype was associated with CAD with OR=2.79(1.54 to 5.05) and p<0.007. The CYP1B1 rs1056827 'A' allele was associated with CAD with OR = 2.30 (1.55 to 3.42) and p< 0.0001. Our results indicated that TNF-α 1800629 gene polymorphism was strongly associated with hypercholesteremia (p<0.0009), HDL (p<0.0001), TGL (p<0.039), hypertension (p<0.0001), and smoking (p<0.0001) in patients with Coronary Artery Disease. Similar correlations of CYP1B1 rs1056827 genotypes were reported with cholesterol (p<0.020), HDL (p<0.002), LDL (p<0.006), hypertension (p<0.03), and smoking (p<0.005). CONCLUSION:It was reported that the GA genotype of the CYP1B1 rs1056827 G>T was strongly associated with susceptibility to Coronary Artery Disease with OR= 2.21(1.17 to 4.15)) and p<0.013, and similarly, its A allele was associated with predisposition to CAD with OR = 2.30 (1.55 to 3.42) and p< 0.0001. Our results indicated that TNF-α 1800629 gene polymorphism is not associated with predisposition to Coronary Artery Disease. Nevertheless, these results should be taken with caution and further validated with larger-scale studies before being introduced in the clinical setting.
10.2174/1871529X22666211221151830
Avenanthramide C Suppresses Matrix Metalloproteinase-9 Expression and Migration Through the MAPK/NF- κB Signaling Pathway in TNF-α-Activated HASMC Cells.
Park Junyoung,Choi Hyunju,Abekura Fukushi,Lim Hak-Seong,Im Jong-Hwan,Yang Woong-Suk,Hwang Cher-Won,Chang Young-Chae,Lee Young-Choon,Park Nam Gyu,Kim Cheorl-Ho
Frontiers in pharmacology
In oat ingredients, flavonoids and phenolic acids are known to be the most important phenolic compounds. In phenolic compounds, wide-ranging biological responses, including antioxidative, anti-inflammatory, anti-allergic, and anti-cancer properties, were reported. Avenanthramide C (Avn C), a component of the phenolic compound of oats, has been reported to be highly antioxidant and anti-inflammatory, but its role in an anti-atherosclerosis response is unknown. The aim of this research was to assess the effect of Avn C on expression of MMP-9 on TNF-α-activated human arterial smooth-muscle cells (HASMC) and signaling involved in its anti-atherosclerosis activity. HASMC cells are known to produce inflammatory cytokines involving IL-6, IL-1β, and TNF-α during arteriosclerosis activity. Avn C specifically reduced IL-6 secretion in HASMC cells. Furthermore, we investigated whether Avn C could inhibit NF-κB nuclear protein translocation. Avn C suppressed nuclear protein translocation of NF-κB in TNF-α-stimulated HASMCs. The MMP-9 enzyme activity and expression are controlled through the MAPKs signaling path during the Avn C treatment. We confirmed that the levels of wound healing (-value = 0.013, * < 0.05) and migration (-value = 0.007, ** < 0.01) are inhibited by 100 ng/ml TNF-α and 100 μM Avn C co-treated. Accordingly, Avn C inhibited the expression of MMP-9 and cell migration through the MAPK/NF-κB signaling pathway in TNF-α-activated HASMC. Therefore, Avn C can be identified and serve as disease prevention material and remedy for atherosclerosis.
10.3389/fphar.2021.621854
Association between miR-146a and Tumor Necrosis Factor Alpha (TNF-α) in Stable Coronary Artery Disease.
Medicina (Kaunas, Lithuania)
: Tumor necrosis factor alpha (TNF-α) is proatherogenic and associated with the risk of acute ischemic events, although the mechanisms that regulate TNF-α expression in stable coronary artery disease (SCAD) are not fully understood. We investigated whether metabolic, inflammatory, and epigenetic (microRNA (miRNA)) markers are associated with TNF-α expression in SCAD. : Patients with SCAD were prospectively recruited and their metabolic and inflammatory profiles were assessed. TNF-α levels were assessed using an enzyme-linked immunosorbent assay. The relative expression of six circulating miRNAs associated with the regulation of inflammation and/or atherosclerosis was determined. : Of the 24 included patients with the mean age of 65 (9) years, 88% were male, and 54% were diabetic. The TNF-α levels were (median (interquartile range)) 1.0 (0.7-1.1) pg/mL. The percentage of glycosylated hemoglobin ( = 0.418, = 0.042), serum triglyceride levels ( = 0.429, = 0.037), and C-reactive protein levels ( = 0.407, = 0.048) were positively correlated with TNF-α levels. Of the candidate miRNAs, miR-146a expression levels were negatively correlated with TNF-α levels (as indicated by = 0.500, = 0.035 for correlation between delta cycle threshold (ΔC) miR-146a and TNF-α levels). In multivariate analysis, serum triglyceride levels and miR-146a expression levels were independently associated with TNF-α levels. miR-146 expression levels were not associated with metabolic or other inflammatory parameters and were negatively correlated with the number of coronary vessels with obstructive disease (as indicated by = 0.556, = 0.017 for correlation between ΔC miR-146a and number of diseased vessels). : miR-146a expression levels were negatively correlated with TNF-α levels in patients with SCAD, irrespective of other metabolic or inflammatory markers, and with the severity of coronary artery disease. The results add to the knowledge on the role of miR-146a in TNF-α-based inflammation in SCAD and support future research on the potential therapeutic use of miR-146a in such a clinical scenario.
10.3390/medicina57060575
Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor.
Pang Kuin Tian,Ghim Mean,Liu Chenghao,Tay Hui Min,Fhu Chee Wai,Chia Rui Ning,Qiu Beiying,Sarathchandra Padmini,Chester Adrian H,Yacoub Magdi H,Wilkinson Fiona L,Weston Ria,Warboys Christina M,Hou Han Wei,Weinberg Peter D,Wang Xiaomeng
Frontiers in cell and developmental biology
Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied . Plasma of 37-week-old mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.
10.3389/fcell.2021.706143
Omarigliptin Prevents TNF-α-Induced Cellular Senescence in Rat Aorta Vascular Smooth Muscle Cells.
Chemical research in toxicology
Cellular senescence is one of the most significant factors involved in aging and age-related diseases. Senescence of vascular smooth muscle cells (VSMCs) adversely affects the function of the cardiovascular system and contributes to the development of atherosclerosis, hypertension, and other cardiovascular diseases. Glucagon-like peptide-1 (GLP-1) is an important incretin hormone involved in insulin release and vascular tone. GLP-1 is quickly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Omarigliptin is a new DPP-4 inhibitor that has demonstrated anti-inflammatory and antioxidative stress properties. In the present study, we investigated the effects of the selective DPP-4 inhibitor omarigliptin (OMG) on VSMCs exposed to insult from tumor necrosis factor-α (TNF-α), one of the main inflammatory signaling molecules involved in cellular senescence. We found that OMG could suppress TNF-α-induced expression of pro-inflammatory cytokines (interleukin-1β (IL-1β), IL-6, and IL-8) and inhibit oxidative stress by reducing the production of HO and protein carbonyl. OMG ameliorated the increase in senescence-associated β-galactosidase (SA-β-gal) and telomerase activity induced by TNF-α. The plasminogen activator inhibitor-1 (PAI-1)/p53/p21 pathway is a key inducer of cellular senescence. OMG ameliorated the acetylation of p53 at lysine 382 (K382) and subsequent activation of p21 via inhibition of PAI-1. Importantly, our experiments revealed that blockage of silent information-regulator 1 (SIRT1) abolished the inhibitory effects of OMG on p53 acetylation, SA-β-gal activity, and telomerase activity in VSMCs. These results suggest that OMG may have the potential to delay or prevent the progression of age-related cardiovascular diseases by modulating the activity of SIRT1.
10.1021/acs.chemrestox.1c00076
Natural Compound Resveratrol Attenuates TNF-Alpha-Induced Vascular Dysfunction in Mice and Human Endothelial Cells: The Involvement of the NF-κB Signaling Pathway.
Nallasamy Palanisamy,Kang Zi Yae,Sun Xiaolun,Anandh Babu Pon Velayutham,Liu Dongmin,Jia Zhenquan
International journal of molecular sciences
Resveratrol, a natural compound in grapes and red wine, has drawn attention due to potential cardiovascular-related health benefits. However, its effect on vascular inflammation at physiologically achievable concentrations is largely unknown. In this study, resveratrol in concentrations as low as 1 μm suppressed TNF-α-induced monocyte adhesion to human EA.hy926 endothelial cells (ECs), a key event in the initiation and development of atherosclerosis. Low concentrations of resveratrol (0.25-2 μm) also significantly attenuated TNF-α-stimulated mRNA expressions of MCP-1/CCL2 and ICAM-1, which are vital mediators of EC-monocyte adhesion molecules and cytokines for cardiovascular plaque formation. Additionally, resveratrol diminished TNF-α-induced IκB-α degradation and subsequent nuclear translocation of NF-κB p65 in ECs. In the animal study, resveratrol supplementation in diet significantly diminished TNF-α-induced increases in circulating levels of adhesion molecules and cytokines, monocyte adhesion to mouse aortic ECs, F4/80-positive macrophages and VCAM-1 expression in mice aortas and restored the disruption in aortic elastin fiber caused by TNF-α treatment. The animal study also confirmed that resveratrol blocks the activation of NF-κB In Vivo. In conclusion, resveratrol at physiologically achievable concentrations displayed protective effects against TNF-α-induced vascular endothelial inflammation in vitro and In Vivo. The ability of resveratrol in reducing inflammation may be associated with its role as a down-regulator of the NF-κB pathway.
10.3390/ijms222212486
Porcine coronary arteries: immunohistochemical profile of TNF-alpha, IL-1beta, TGF-beta1 and ICAM-1.
Folia morphologica
BACKGROUND:In our study we used immunohistochemical technique to demonstrate the presence of the cytokines tumour necrosis factor alpha (TNF-α), interleukin 1beta (IL-1β), transforming growth factor beta1 (TGF-β1) and intercellular adhesion molecule-1 (ICAM-1) in porcine coronaries even in physiological conditions. MATERIALS AND METHODS:Inflammatory cytokines are polypeptide mediators which act as a communication signal between immune system cells and other types of cellsin different organs and tissues, both in human and pig coronary circulation. RESULTS:Our results show that pro-inflammatory cytokines TNF-α, IL-1β, TGF-β1 and ICAM-1 are also present in the medium tunica of the coronary arteries under physiological conditions. These results may be compared with those found in coronary atherosclerosis, where the increase in TNF-α has a dramatic effect on the function of the left ventricle, and the high value of IL-1 correlates directly with the extent of myocardial necrosis. In our study we observe the damage and activation of endothelial cells; this induces endothelial dysfunction by accumulation and oxidation of low density lipoproteins (LDL). The formation of oxidized LDL could play a central role in the amplification of the inflammatory response causing an increased expression of pro-inflammatory cytokines which promotes leukocyte recruitment in the intimal layer. These leukocytes, after the adhesion to the endothelium, penetrate the intimate tunic. CONCLUSIONS:Therefore inflammatory processes promote the onset and evolution of atheroma and the development of thrombotic complications.
10.5603/FM.a2021.0137
Effects of Ruanmailing in Blocking Early Stages of Atherosclerosis by TNF- Regulation via Kir2.1.
Evidence-based complementary and alternative medicine : eCAM
Objective:Ruanmailing oral solution consists of 16 herbs, has anti-lipid peroxidation activity, protects vascular endothelial cells, and improves vascular elasticity. It is an effective drug for the treatment of atherosclerosis (AS). The objective of this study was to investigate the mechanism underlying the antiatherosclerotic effects of Ruanmailing oral solution. Methods:Macrophages were isolated, cultured, and divided into the macrophage control; macrophage foam cell; and low-, medium-, and high-concentration Ruanmailing groups. Cell proliferation was analyzed by cell counting kit-8 (CCK-8) assay, and the expression levels of inward-rectifier potassium ion channel 2.1 (Kir2.1) and tumor necrosis factor (TNF)- were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. Results:CCK-8 assay results showed that the tested concentrations of Ruanmailing solution did not affect macrophage proliferation. RT-PCR and Western blot assays indicated that TNF- expression increased significantly with the formation of macrophage foam cells ( < 0.05). In addition, significant decreases in Kir2.1 and TNF- expression were observed following treatment with various concentrations of Ruanmailing ( < 0.05). Conclusion:Based on the results, Ruanmailing affects macrophage foam cell formation by regulating Kir2.1 expression, which in turn reduces TNF- expression and exerts antiatherosclerotic effects. These findings provide a scientific basis for the use of traditional Chinese medicine for AS treatment.
10.1155/2022/2836880
ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway.
Open medicine (Warsaw, Poland)
The dysfunction and apoptosis of vascular endothelial cells are the initiating links in the formation of atherosclerosis. N6-methyladenosine (m6A) is an extremely extensive RNA methylation modification and its abnormality leads to the occurrence of various human diseases. In this study, we explored the effects of demethylase -ketoglutarate-dependent dioxygenase ALKB homolog 5 (ALKBH5) on TNF-α-induced apoptosis of human umbilical vein endothelial cells (HUVECs). In TNF-α-treated HUVECs, the expression of ALKBH5 was significantly decreased. ALKBH5 overexpression promoted the proliferation and inhibited the apoptosis in TNF-α-treated HUVECs, suggesting that ALKBH5 had a protective effect on cell damage induced by TNF-α. Importantly, ALKBH5 promoted the expression of Bcl-2 in HUVECs. Bcl2 overexpression reduced the expression of Gadd45, Bax, and p21, which are transcriptionally activated by p53. But the expression of p53 has not been significantly affected, indicating that Bcl2 might regulate the apoptosis by inhibiting p53 downstream targets. In addition, ALKBH5 overexpression significantly increased the level of pri-miR-7 and decreased the level of miR-7. In conclusion, ALKBH5 attenuated the TNF-α-induced cell injury via promoting Bcl2 expression. Our research expands the understanding of the progression mechanism of atherosclerosis and provides a potential strategy for the protection of vascular endothelial injury.
10.1515/med-2022-0484