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    Kaempferol Alleviates Angiotensin II-Induced Cardiac Dysfunction and Interstitial Fibrosis in Mice. Liu Yuan,Gao Lu,Guo Sen,Liu Yuzhou,Zhao Xiaoyan,Li Ran,Yan Xiaofei,Li Yunpeng,Wang Shuai,Niu Xiaoyu,Yao Liantao,Zhang Yanzhou,Li Ling,Yang Haibo Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Endothelial-to-mesenchymal transition (EndMT) is a mechanism that promotes cardiac fibrosis induced by Angiotensin II (AngII). Kaempferol (KAE) is a monomer component mainly derived from the rhizome of Kaempferia galanga L. It shows anti-inflammatory, anti-oxidative, anti-microbial and anti-cancer properties, which can be used in the treatment of cancer, cardiovascular diseases, infection, etc. But, its effects on the development of cardiac remodelling remain completely unknown. The aim of the present study was to determine whether KAE attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and cardiac hypertrophy induced by AngII infusion in mice in vivo. METHODS:Male wild-type mice aged 8-10 weeks with or without KAE were subjected to AngII or saline, to induce fibrosis or as a control, respectively. Morphological changes, echocardiographic parameters, histological analyses, and hypertrophic markers were also used to evaluate hypertrophy. RESULTS:KAE prevented and reversed cardiac remodelling induced by AngII. The KAE in this model exerted no basal effects but attenuated cardiac fibrosis, hypertrophy and dysfunction induced by AngII. Both in vivo and in vitro experiments demonstrated that Ang II infusion or TGF-β induced EndMT can be reduced by KAE and the proliferation and activation of cardiac fibroblasts (CFs) can be inhibited by KAE. CONCLUSIONS:The results suggest that KAE prevents and reverses ventricular fibrosis and cardiac dysfunction, providing an experimental basis for clinical treatment on ventricular fibrosis. 10.1159/000484304
    Deciphering the Mechanism of the Anti-Hypertensive Effect of Isorhynchophylline by Targeting Neurotransmitters Metabolism of Hypothalamus in Spontaneously Hypertensive Rats. Li Yuan,Yu Ruixue,Zhang Dan,Yang Wenqing,Hou Qingqing,Li Yunlun,Jiang Haiqiang ACS chemical neuroscience Essential hypertension is a major risk factor for cardiovascular disease that can lead eventually to structural and functional alterations in the brain. Accumulating evidence has suggested that the increased activities in renin-angiotensin system and sympathetic nerve participated in the pathogenesis of hypertension that is related to the imbalance between neurotransmitters. The potential role in essential hypertension arising from alterations of neurotransmitters in the central nervous system remains understudied. Isorhynchophylline is a major oxindole alkaloid extracted from , which has been widely used for treating hypertension and neurodegenerative diseases. Whether isorhynchophylline acts on neurotransmitters to lower blood pressure has been hypothesized but rarely demonstrated unequivocally. Here, we studied the metabolic neurotransmitter profiles in the hypothalamus using a targeted metabolomic approach in spontaneously hypertensive rats after isorhynchophylline intervention. Our study demonstrated that isorhynchophylline exhibited a strong anti-hypertensive effect in spontaneously hypertensive rats by improving the neurotransmitter imbalance in the hypothalamus and inhibiting the overactivation of the renin-angiotensin system and sympathetic nerve system. Overall, this study played an essential role in enhancing our understanding of the mechanism of isorhynchophylline in essential hypertension and in providing theoretical evidence for future research and clinical application. 10.1021/acschemneuro.9b00699
    Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension. Li Xiaojie,Lin Yuhan,Zhou Hongyu,Li Yao,Wang Aimei,Wang Hongxin,Zhou Ming-Sheng Clinical and experimental hypertension (New York, N.Y. : 1993) Puerarin, a major isoflavonoid compound from Chinese herb Kudzu roots, has been widely used for the treatment of hypertensive and cardiovascular diseases in China. Here, we investigated puerarin's beneficial effects on the cardiovascular system in angiotensin (Ang) II-induced hypertensive rats. Sprague-Dawley rats were treated with Ang II for 5 days or with puerarin for 10 days followed by Ang II and puerarin for 5 days. Endothelium-dependent relaxation (EDR) to acetylcholine was determined using an organ chamber bath. Ang II increased the systolic blood pressure (SBP: 178 ± 5 mmHg vs. 112 ± 3 mmHg in control, p < 0.05), aortic (30%, p < 0.05), and left ventricular (LV) weight (23%); puerarin reduced SBP (160 ± 2 mmHg, p < 0.05), aortic, and left ventricular weight in Ang II-infused rats. Puerarin also reduced aortic medial thickness and myocardial cell surface area in Ang II-infused rats. Compared with control rats, Ang II infused rats exhibited an impaired EDR with reduction in the protein expression of phosphor-eNOS at Ser 1177 and an increase in the expression of gp91phox (85%), p22phox (113%), transforming growth factor β1 (145%) and vascular cell adhesion molecule 1 (82%). Puerarin improved EDR and reversed the changes in Ang II-induced protein expression of above molecules. Our results demonstrate that in Ang II-induced hypertensive rats, puerarin protects against endothelial dysfunction and end organ damage with a mild reduction in SBP, and that the cardiovascular beneficial effects of puerarin may be in part attributed to its anti-oxidant and upregulation of phosphor-eNOS. 10.1080/10641963.2016.1200603
    Traditional Chinese Medicine in Treating Hypertension. Circulation. Cardiovascular quality and outcomes 10.1161/CIRCOUTCOMES.121.008723
    Pathophysiology of Hypertensive Heart Disease: Beyond Left Ventricular Hypertrophy. Nwabuo Chike C,Vasan Ramachandran S Current hypertension reports PURPOSE OF REVIEW:Given that the life expectancy and the burden of hypertension are projected to increase over the next decade, hypertensive heart disease (HHD) may be expected to play an even more central role in the pathophysiology of cardiovascular disease (CVD). A broader understanding of the features and underlying mechanisms that constitute HHD therefore is of paramount importance. RECENT FINDINGS:HHD is a condition that arises as a result of elevated blood pressure and constitutes a key underlying mechanism for cardiovascular morbidity and mortality. Historically, studies investigating HHD have primarily focused on left ventricular (LV) hypertrophy (LVH), but it is increasingly apparent that HHD encompasses a range of target-organ damage beyond LVH, including other cardiovascular structural and functional adaptations that may occur separately or concomitantly. HHD is characterized by micro- and macroscopic myocardial alterations, structural phenotypic adaptations, and functional changes that include cardiac fibrosis, and the remodeling of the atria and ventricles and the arterial system. In this review, we summarize the structural and functional alterations in the cardiac and vascular system that constitute HHD and underscore their underlying pathophysiology. 10.1007/s11906-020-1017-9
    Endogenous Taurine Downregulation Is Required for Renal Injury in Salt-Sensitive Hypertensive Rats via CBS/HS Inhibition. Huang Pan,Huang Yaqian,Lv Boyang,Zhang Heng,Liu Jia,Yang Guosheng,Tao Yinghong,Bu Dingfang,Wang Guang,Du Junbao,Jin Hongfang Oxidative medicine and cellular longevity Although taurine is known to exert an antihypertensive effect, it is unclear whether it is involved in the mechanism for hypertension-related target organ injury. To reveal the role of endogenous taurine in renal injury formation during salt-sensitive hypertension and clarify its mechanisms, both salt-sensitive Dahl rats and salt-resistant SS-13BN rats were fed a high-salt diet (8% NaCl) and given 2% taurine for 6 weeks. Rat systolic blood pressure (SBP) was measured by the tail-cuff method and artery catheterization. Kidney ultrastructure was observed under an electron microscope. Taurine content and mRNA and protein levels of taurine synthases, cysteine dioxygenase type 1 (CDO1) and cysteine sulfinic acid decarboxylase (CSAD), were decreased in Dahl rats fed a high-salt diet. However, taurine supplementation and the resulting increase in renal taurine content reduced the increased SBP and improved renal function and structural damage in high-salt diet-fed Dahl rats. In contrast, taurine did not affect SS-13BN SBP and renal function and structure. Taurine intervention increased the renal HS content and enhanced cystathionine--synthase (CBS) expression and activity in Dahl rats fed a high-salt diet. Taurine reduced the renin, angiotensin II, and aldosterone contents and the levels of oxidative stress indices in Dahl rat renal tissues but increased antioxidant capacity, antioxidant enzyme activity, and protein expression. However, taurine failed to achieve this effect in the renal tissue of SS-13BN rats fed a high-salt diet. Pretreatment with the CBS inhibitor HA or renal CBS knockdown inhibited HS generation and subsequently blocked the effect of taurine on renin, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) levels in high-salt-stimulated Dahl renal slices. In conclusion, the downregulation of endogenous taurine production resulted in a decrease in the renal CBS/HS pathway. This decrease subsequently promoted renin-angiotensin-aldosterone system (RAAS) activation and oxidative stress in the kidney, ultimately contributing to renal injury in salt-sensitive Dahl rats. 10.1155/2021/5530907
    Mosaic theory revised: inflammation and salt play central roles in arterial hypertension. Cellular & molecular immunology The mosaic theory of hypertension was advocated by Irvine Page ~80 years ago and suggested that hypertension resulted from the close interactions of different causes. Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury. Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension. Sodium intake is indispensable for normal body function but can be detrimental when it exceeds dietary requirements. Recent data show that sodium levels also modulate the function of monocytes/macrophages, dendritic cells, and different T-cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome due to high-salt intake. The purpose of this review is to propose a revised and extended version of the mosaic theory by summarizing and integrating recent advances in salt, immunity, and hypertension research. Salt and inflammation are placed in the middle of the mosaic because both factors influence each of the remaining pieces. 10.1038/s41423-022-00851-8
    regulates inflammasome-mediated hypertensive cardiac inflammation and fibrosis . Bioengineered Hypertension is a severe public health problem that induces cardiac injury with alterations of gene expressions. The current study sought to evaluate the mechanism of ( in NOD-like receptor family pyrin domain containing 3 () inflammasome-mediation of cardiac inflammation and hypertensive cardiac fibrosis. Firstly, hypertensive mouse models were established using angiotensin II (Ang II), followed by agomir treatment. Subsequently, mouse blood pressure and basic cardiac function indexes, histopathological changes, and cardiac fibrosis were all determined, in addition to detection of factors related to inflammation and fibrosis. Additionally, mice cardiac fibroblasts (CFs) were isolated and treated with Ang II. The binding relationship of and thioredoxin-interacting protein () was predicted and testified, while the interaction of and was detected by means of a co-immunoprecipitation assay. It was found that was poorly-expressed in Ang II-treated mice and further exerted cardioprotective effects against hypertensive heart diseases. Moreover, over-expression of resulted in inhibition of inflammatory infiltration and almost eliminated cardiac fibrosis, as evidenced by decreased Collagen (COL)-I, COL-III, a-smooth muscle actin, , tumor necrosis factor-α, and interleukin-6. Mechanically, inhibited expression to block the binding of and . On the other hand, up-regulation reversed the protective role of over-expression in CFs. Collectively, our findings indicated that over-expression inhibited expression to block the binding of and , thereby alleviating hypertensive cardiac inflammation and fibrosis. 10.1080/21655979.2021.2024956
    Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Krishnan Shalini M,Ling Yeong H,Huuskes Brooke M,Ferens Dorota M,Saini Narbada,Chan Christopher T,Diep Henry,Kett Michelle M,Samuel Chrishan S,Kemp-Harper Barbara K,Robertson Avril A B,Cooper Matthew A,Peter Karlheinz,Latz Eicke,Mansell Ashley S,Sobey Christopher G,Drummond Grant R,Vinh Antony Cardiovascular research AIMS:Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension. METHODS AND RESULTS:C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25-40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20-25%). None of the above parameters were altered by MCC950 in normotensive mice. CONCLUSION:MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy. 10.1093/cvr/cvy252
    Role of PDGFs/PDGFRs signaling pathway in myocardial fibrosis of DOCA/salt hypertensive rats. Fan Bin,Ma Likun,Li Qian,Wang Lin,Zhou Junling,Wu Jiawei International journal of clinical and experimental pathology This study aimed to investigate the role of PDGF/PDGFR signaling pathway in myocardial fibrosis of desoxycorticosterone (DOCA) induced salt-sensitive hypertensive rats and explore the influence of PDGF/PDGFR signaling pathway on fibroblasts and myofibroblasts in the heart. 60 male SD rats underwent right nephrectomy and bred with 1% sodium chloride and 0.1% potassium chloride for 4 weeks, and then randomly divided into 3 groups (CON group, DOCA group and DOCA+IMA group). Results showed that: 1) 14 and 28 days after intervention, the SBP in DOCA and DOCA+IMA group was significantly higher than that in CON group. At days 28, the severity of myocardial fibrosis and PVCA/VA ratio in DOCA group were significantly increased when compared with CON group. The severity of myocardial fibrosis and PVCA/VA ratio in DOCA+IMA group were markedly lower than those in DOCA group although they were higher than those in CON group. 2) At days 14, the mRNA expressions of PDGFRα and PDGFRβ in DOCA group were significantly higher than CON and DOCA+IMA group. At days 28, the mRNA expressions of PDGFRβ, FSP-1, α-SMA, procollagen I and procollagen III in DOCA group were significantly higher than those in CON group. In addition, in a specific group, the PDGFRβ mRNA expression was higher than the PDGFRα mRNA expression. In DOCA+IMA group, the mRNA expressions of PDGFRβ, FSP-1, α-SMA, procollagen I and procollagen III were markedly reduced when compared with DOCA group. 3) At 14 days, the protein expressions of PDGFRα and PDGFRβ in DOCA group were significantly higher than those in CON group. The PDGFRα protein expression in DOCA+IMA group was markedly lower than that in DOCA group. At days 28, the protein expressions of PDGFRα and PDGFRβ in DOCA group were significantly increased when compared with CON group. The protein expressions of PDGFRα and PDGFRβ in DOCA+IMA group were significantly lower than those in DOCA group. At day 28, the cardiac interstitium mainly contained vimentin positive fibroblasts, and α-SMA positive cells were less identified in CON group. In DOCA group, α-SMA positive fibroblasts (spindle-shaped) increased significantly, but the myofibroblasts reduced significantly in DOCA+IMA group when compared with DOCA group. 4) PDGFRα protein expression was observed in fibroblasts and myofibroblasts, but not in VSMCs. PDGFRβ protein expression was noted in not only fibroblasts and myofibroblasts but also VSMCs. Thus, During myocardial fibrosis of DOCA induced salt-sensitive hypertensive rats, PDGFRα acts at early stage, but PDGFRβ functions in the whole process. PDGFRα and PDGFRβ expressions increase in fibroblasts and myofibroblasts, suggesting that PDGF/PDGFR signaling pathway is involved in the myocardial fibrosis via stimulating fibroblasts to proliferate and transform into myofibroblasts.