Comparison of the Clinical Value of miRNAs and Conventional Biomarkers in AMI: A Systematic Review.
Wang Baofu,Li Yang,Hao Xuezeng,Yang Jingjing,Han Xiaowan,Li Haiyan,Li Tong,Wang Dayang,Teng Yu,Ma Liang,Li Yao,Zhao Mingjing,Wang Xian
Frontiers in genetics
This study aimed to compare the clinical value of the peak time point and area under the curve (AUC) of miRNAs and conventional biomarkers in acute myocardial infarction (AMI). A literature search was carried out in PubMed, Web of Science, Embase, and Cochrane systematically. Screening studies, extracting data, and assessing article quality were performed independently by two researchers. Also, the names of miRNAs in the included studies were standardized by the miRBase database. A total of 40 studies, encompassing 6,960 participants, were included in this systematic review. The samples of circulating miRNAs were mainly from the plasma. The results of this systematic review displayed that miR-1-3p, miR-19b-3p, miR-22-5p, miR-122-5p, miR-124-3p, miR-133a/b, miR-134-5p, miR-150-5p, miR-186-5p, miR-208a, miR-223-3p, miR-483-5p, and miR-499a-5p reached peak time earlier and showed a shorter time window than the conventional biomarkers despite the different collection times of initial blood samples. miR-1-3p, miR-19b-3p, miR-133a/b, miR-208a/b, miR-223-3p, miR-483-5p, and miR-499a-5p were shown to be more valuable than classical biomarkers for the early diagnosis of AMI, and these miRNAs appeared to have the most potential biomarkers within 4 h of the onset of symptoms except miR-133a/b and miR-208b. Moreover, combined miRNAs or miRNAs combined with classical biomarkers could compensate for the deficiency of single miRNA and conventional biomarker in sensitivity or specificity for an optimal clinical value. miR-1-3p, miR-19b-3p, miR-208a, miR-223-3p, miR-483-5p, and miR-499a-5p are promising biomarkers for AMI due to their satisfactory diagnostic accuracy and short time window (within 4 h of the onset of symptoms).
10.3389/fgene.2021.668324
Human umbilical cord mesenchymal stem cell-derived extracellular vesicles loaded with miR-223 ameliorate myocardial infarction through P53/S100A9 axis.
Genomics
Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been proposed as a promising strategy for myocardial infarction (MI). This study aims to explore the mechanism of human umbilical cord MSCs (hucMSCs)-derived EVs loaded with miR-223 on MI. Inflammation, cell biological functions, and fibrosis in vitro were measured. Furthermore, MI rat models were established to verify the role of EVs-miR-223 in vivo. The binding relationship between miR-223 and P53 was confirmed. ChIP assay was utilized to observe the combination of P53 and S100A9. The suppressed fibrosis of cardiomyocytes occurred with cells overexpressing miR-223. MiR-223 contributed to the angiogenesis of HUVECs. P53 was a target gene of miR-223. In vivo, miR-223 relieved myocardial fibrosis and inflammation infiltration, and promoted the angiogenesis in MI rats. HucMSC-derived EVs loaded with miR-223 mitigates MI and promotes myocardial repair through the P53/S100A9 axis, manifesting the underlying therapy values of hucMSC-derived EVs loaded with miR-223 in MI.
10.1016/j.ygeno.2022.110319
Sox9 Promotes Cardiomyocyte Apoptosis After Acute Myocardial Infarction by Promoting miR-223-3p and Inhibiting MEF2C.
Molecular biotechnology
Acute myocardial infarction (AMI) is a severe and even fatal cardiovascular disease. The effect of transcription factors on AMI is intensively explored. Our experiment attempts to probe the role of Sox9 in cardiomyocyte apoptosis after AMI. AMI cell model was established in AC16 cells by hypoxia treatment. Cell viability and apoptosis were assessed. Then, the levels of BAX, Bcl-2, Sox9, miR-223-3p, and MEF2C were detected. The binding relation between Sox9 and miR-223-3p and between miR-223-3p and MEF2C was verified. The expression of miR-223-3p was upregulated using the miR-223-3p mimic, and collaborative experiments were conducted as si-Sox9 or si-MEF2C was transfected into cells to inhibit the expression of Sox9 or MEF2C. Sox9 was highly expressed in cardiomyocyte apoptosis after hypoxia, while Sox9 silencing protected hypoxia-treated cardiomyocytes from apoptosis by enhancing cell viability, quenching apoptosis, and reducing activity of caspase-3 and caspase-9. Essentially, Sox9 bound to the miR-223-3p promoter region to upregulate its expression. miR-223-3p targeted MEF2C transcription. miR-223-3p overexpression and MEF2C silencing could counteract the suppressive role of Sox9 silencing in hypoxia-treated cardiomyocyte apoptosis. Sox9 exacerbated hypoxia-induced cardiomyocyte apoptosis by promoting miR-223-3p expression and inhibiting MEF2C transcription.
10.1007/s12033-022-00471-7
MiR-223-3p affects myocardial inflammation and apoptosis following myocardial infarction via targeting FBXW7.
Journal of thoracic disease
Background:Myocardial infarction (MI) is one of the main causes of disability and death in the world, leading to myocarditis and cardiomyocyte apoptosis. Studies have shown that microRNA (miRNA) is involved in myocarditis and apoptosis. The main purpose of this study was to explore the regulatory mechanism of miR-223-3p on myocarditis and apoptosis after MI. Methods:We cultured H9c2 cells and detected the expression of miR-223-3p in cells treated with different concentrations of HO. Sprague Dawley (SD) rats were fed with normal diet, constructed an MI model and detect the expression of miR-223-3p in heart tissue. Overexpression or inhibition of miR-223-3p was conducted in MI model cells , and the contents of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in cell supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was detected by flow cytometry. Luciferase activity assay was used to detect the targeting relationship between miR-223-3p and , and the expression of in cells was also detected. Overexpression of miR-223-3p was performed in MI rats to detect the expression of inflammatory factors, , and apoptosis in rat cardiac tissue. Results:The expression of miR-223-3p was down regulated in MI models established and . Overexpression of miR-223-3p can inhibit inflammatory response and apoptosis in H9c2 cells and cardiac tissues. It was revealed that miR-223-3p can inhibit the expression of , reduce myocarditis and apoptosis after MI, and improve cardiac function. Conclusions:It is possible that miR-223-3p reduces myocarditis and apoptosis after MI and improves cardiac function by targeted inhibition of expression.
10.21037/jtd-22-82
ZNF561-AS1 Regulates Cell Proliferation and Apoptosis in Myocardial Infarction Through miR-223-3p/NLRP3 Axis.
Cell transplantation
Long non-coding RNAs (lncRNAs) have been widely recognized as important regulators in myocardial infarction (MI) and other heart diseases. Our study aimed to investigate the mechanism and biological function of an unknown lncRNA zinc finger protein 561 antisense RNA 1 (ZNF561-AS1) in MI. After confirming the MI model was successful, we applied reverse transcription quantitative polymerase chain reaction and Western blot (WB) and found that the expression of NLR family pyrin domain containing 3 (NLRP3), interleukin (IL)-1β, and IL-18 was substantially increased in infarct and border zones of MI mice heart at 24 h and 72 h compared with that in sham-operated models. Moreover, we found that NLRP3 expression was promoted in hypoxia human cardiomyocytes (HCMs). Through cell function assays including CCK-8, 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry, and TdT-mediated dUTP Nick-End Labeling (TUNEL), supported by WB analysis, we verified that silencing of NLRP3 facilitated proliferation but impeded apoptosis of hypoxia-induced myocardial cell. Moreover, Ago2-RIP and RNA pull-down assays displayed that NLRP3 could combine with miR-223-3p. Luciferase reporter assays further confirmed that NLRP3 was directly targeted by miR-223-3p. Simultaneously, we found that miR-223-3p was the downstream gene of ZNF561-AS1. In addition, we conducted a series of rescue experiments to affirm that ZNF561-AS1 regulated cell proliferation and apoptosis in MI through miR-223-3p/NLRP3 axis.
10.1177/09636897221077928
miR-146a-5p, miR-223-3p and miR-142-3p as Potential Predictors of Major Adverse Cardiac Events in Young Patients with Acute ST Elevation Myocardial Infarction-Added Value over Left Ventricular Myocardial Work Indices.
Diagnostics (Basel, Switzerland)
Acute ST elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality worldwide despite continuous advances in diagnostic, prognostic and therapeutic methods. Myocardial work (MW) indices and miRNAs have both emerged as potential prognostic markers in acute coronary syndromes in recent years. In this study we aim to assess the prognostic role of myocardial work indices and of a group of miRNAs in young patients with STEMI. We enrolled 50 young patients (<55 years) with STEMI who underwent primary PCI and 10 healthy age-matched controls. We performed standard 2D and 3D echocardiography; we also calculated left ventricular global longitudinal strain (GLS) and the derived myocardial work indices. Using RT-PCR we determined the plasmatic levels of six miRNAs: miR-223-3p, miR-142-3p, miR-146a-5p, miR-125a-5p, miR-486-5p and miR-155-5p. We assessed the occurrence of major adverse cardiac events (MACE) at up to one year after STEMI. Out of 50 patients, 18% experienced MACE at the one-year follow-up. In a Cox univariate logistic regression analysis, myocardial work indices were all significantly associated with MACE. The ROC analysis showed that GWI, GCW and GWE as a group have a better predictive value for MACE than each separately (AUC 0.951, p = 0.000). Patients with higher miRNAs values at baseline (miR-223-3p, miR-142-3p and miR-146a-5p) appear to have a higher probability of developing adverse events at 12 months of follow-up. ROC curves outlined for each variable confirmed their good predictive value (AUC = 0.832, p = 0.002 for miR-223-3p; AUC = 0.732, p = 0.031 for miR-142-3p and AUC = 0.848, p = 0.001 for miR-146a-5p); the group of three miRNAs also proved to have a better predictive value for MACE together than separately (AUC = 0.862). Moreover, adding each of the miRNAs (miR-233, miR-142-3p and miR-146a-5p) or all together over the myocardial work indices in the regression models improved their prognostic value. In conclusion, both myocardial work indices (GWI, GCW and GWE) and three miRNAs (miR-223-3p, miR-142-3p and miR-146a-5p) have the potential to be used as prognostic markers for adverse events after acute myocardial infarction. The combination of miRNAs and MW indices (measured at baseline) rather than each separately has very good predictive value for MACE in young STEMI patients (C-statistic 0.977).
10.3390/diagnostics12081946
MiR-223 and MiR-186 Are Associated with Long-Term Mortality after Myocardial Infarction.
Biomolecules
Background-The identification and stratification of patients at risk of fatal outcomes after myocardial infarction (MI) is of considerable interest to guide secondary prevention therapies. Currently, no accurate biomarkers are available to identify subjects who are at risk of suffering acute manifestations of coronary heart disease as well as to predict adverse events after MI. Non-coding circulating microRNAs (miRNAs) have been proposed as novel diagnostic and prognostic biomarkers in cardiovascular diseases. The aims of the study were to investigate the clinical value of a panel of circulating miRNAs as accurate biomarkers associated with MI and mortality risk prediction in patients with documented MI. Methods and Results-seven circulating plasma miRNAs were analyzed in 67 MI patients and 80 control subjects at a high cardiovascular risk but without known coronary diseases. Multivariate logistic regression analyses demonstrated that six miRNAs were independently associated with MI occurrence. Among them, miR-223 and miR-186 reliably predicted long-term mortality in MI patients, in particular miR-223 (HR 1.57 per one-unit increase, = 0.02), after left ventricular ejection fraction (LVEF) adjustment. Kaplan-Meier survival analyses provided a predictive threshold value of miR-223 expression ( = 0.028) for long-term mortality. Conclusions-Circulating miR-223 and miR-186 are promising predictive biomarkers for long-term mortality after MI.
10.3390/biom12091243
Naringenin promotes angiogenesis of ischemic myocardium after myocardial infarction through miR-223-3p/IGF1R axis.
Regenerative therapy
Introduction:Naringenin exerts a protective effect on myocardial ischemia and reperfusion. It has been reported that miR-223-3p is a potential target for the treatment of myocardial infarction (MI). In view of the unreported correlation between Naringenin and miR-223-3p, this study was designed to confirm that the ameliorative effects of Naringenin on MI is directly related to the regulation of miR-223-3p. Methods:Through electrocardiogram detection, Masson pathological staining and immunohistochemistry of angiogenesis-related factors, alleviative effects of Naringenin on heart function, myocardial injury and angiogenesis in MI mice were observed individually. Hypoxic HUVECs were selected in the experimental model. The cell viability, angiogenesis and migration ability were analyzed to fathom out the pro-angiogenesis potential of Naringenin. The effect of Naringenin on miR-223-3p, as well as the downstream molecular mechanism was verified through bioinformatics analysis and rescue experiments. Results:Naringenin improved heart functions of MI mice, reduced degree of myocardial fibrosis, stimulated expressions of angiogenic factors and down-regulated level of miR-223-3p in myocardial tissue. In experiments, Naringenin increased the viability of hypoxic HUVECs, as well as the abilities of tube formation and migration, and further inhibited the expression of miR-223-3p. In the rescue trial, miR-223-3p mimic reversed the therapeutic effect of Naringenin. Type 1 insulin-like growth factor receptor (IGF1R), as a downstream target gene of miR-223-3p, partially offset the cellular regulatory effects of miR-223-3p after overexpression of IGF1R. Conclusions:Naringenin improves the angiogenesis of hypoxic HUVECs by regulating the miR-223-3p/IGF1R axis, and has the potential to promote myocardial angiogenesis in MI mice.
10.1016/j.reth.2022.07.008
LncRNA FGD5-AS1 reduces cardiomyocyte apoptosis and inflammation by modulating Akt and miR-223-3p expression.
American journal of translational research
OBJECTIVES:Long non-coding RNAs (lncRNAs) are known to be involved in heart development and function. In this study, we aimed to explore the effect of the lncRNA FGD5 antisense RNA 1 (FGD5-AS1) on acute myocardial infarction (AMI) by targeting miR-223-3p. METHODS:An AMI model was established both in vivo and in vitro. The levels of FGD5-AS1, miR-223-3p and inflammatory factors were detected by real-time quantitative reverse transcription PCR. Cardiomyocyte apoptosis was assessed using TdT-mediated dUTP nick-end labeling assay. The protein levels of cleaved caspase-3, Bcl-2 and Bax were examined using Western blot. Cardiac function was evaluated using hemodynamic analysis and hematoxylin-eosin and Masson's trichrome staining. In addition, an underlying competitive endogenous RNA mechanism was revealed by bioinformatics analysis, dual-luciferase reporter assay and rescue experiments. RESULTS:We found decreased expression of FGD5-AS1 in AMI. Furthermore, FGD5-AS1 expression significantly decreased the infarct size, improved cardiac performance and attenuated cardiac fibrosis by reducing myocardial apoptosis and inflammation. miR-223-3p was a direct target of FGD5-AS1. Moreover, miRNA-223-3p directly downregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes. Further experiments demonstrated that FGD5-AS1 modulated Akt activity to reduce myocardial injury through miR-223-3p. CONCLUSION:The FGD5-AS1/miR-223-3p/Akt pathway is involved in AMI, suggesting that FGD5-AS1 may act as a potential biomarker and therapeutic target for AMI.
Platelet Internalization Mediates Ferroptosis in Myocardial Infarction.
Arteriosclerosis, thrombosis, and vascular biology
BACKGROUND:Myocardial cell death is the hallmark of myocardial infarction. In the process of myocardial injury, platelets contribute to the pathogenesis by triggering intense inflammatory responses. Yet, it is still unclear if platelets regulate cardiomyocyte death directly, thereby exacerbating myocardial injury in myocardial infarction. METHODS:We describe a mechanism underlying the correlative association between platelets accumulation and myocardial cell death by using myocardial infarction mouse model and patient specimens. RESULTS:Myocardial infarction induces platelets internalization, resulting in the release of miR-223-3p, a platelet-enriched miRNA. By targeting the ACSL3, miR-223-3p delivered by internalized platelets cause the reduction of stearic acid-phosphatidylcholine in cardiomyocytes. The presence of stearic acid-phosphatidylcholine protects cardiomyocytes against ferroptosis. CONCLUSIONS:Our work reveals a novel mechanism of platelet-mediated myocardial injury, highlighting antiplatelet therapies could potentially represent a multimechanism treatment of myocardial infarction, and implying ferroptosis being considered as novel target for therapeutics.
10.1161/ATVBAHA.122.318161
Expression of microRNA Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease.
Thrombosis and haemostasis
BACKGROUND: New biomarkers are warranted to identify patients with coronary artery disease (CAD) at high risk of recurrent cardiovascular events. It has been reported that the expression of microRNAs (miRs) may influence the development of CAD. OBJECTIVES: We aimed to investigate whether the expression of selected candidate miRs is a predictor of cardiovascular events in a cohort of stable CAD patients. METHODS: We performed a single-center prospective study of 749 stable CAD patients with a median follow-up of 2.8 years. We investigated the expression of nine candidate miRs and their relation to cardiovascular events in this cohort. The primary endpoint was the composite of nonfatal myocardial infarction (MI), stent thrombosis (ST), ischemic stroke, and cardiovascular death. The composite of nonfatal MI and ST was analyzed as a secondary endpoint. Furthermore, nonfatal MI, ST, ischemic stroke, and all-cause mortality were analyzed as individual endpoints. RESULTS: Employing receiver operating characteristic curves, it was shown that compared with traditional cardiovascular risk factors alone, combining the expression of miR-223-3p with existing traditional cardiovascular risk factors increased the predictive value of ST (area under the curve: 0.88 vs. 0.77, = 0.04), the primary composite endpoint (0.65 vs. 0.61, = 0.049), and the secondary endpoint of the composite of nonfatal MI and ST (0.68 vs. 0.62, = 0.04). CONCLUSION: Among patients with CAD, adding miR-223-3p expression to traditional cardiovascular risk factors may improve prediction of cardiovascular events, particularly ST. Clinical trials confirming these findings are warranted.
10.1055/s-0042-1760258
Analysis of Differentially Expressed Murine miRNAs in Acute Myocardial Infarction and Target Genes Related to Heart Rate.
Cell biochemistry and biophysics
OBJECTIVE:This study aims to investigate the expression profile of miRNAs significantly dysregulated after acute myocardial infarction (AMI) and their potential targets. METHODS:After the establishment of a mouse model of AMI, RNA was extracted from mouse infarcted myocardium. Paired-end sequencing was then performed using the Illumina NovaSeq 6000 system to explore the expression profile of miRNAs. Target genes of downregulated differentially expressed miRNAs (DEmiRNAs) were predicted with miRanda (version 3.3a) and TargetScan (version 6.0). Cytoscape was used to construct a DEmiRNA-mRNA regulatory network to show the regulatory relationship. RT-qPCR was performed to measure miR-142a-3p expression in HO-treated rat cardiomyocyte H9c2 cells and heart tissues of MI rats. Cell counting kit-8 and TUNEL assays were conducted to detect H9c2 cell viability and apoptosis. RESULTS:There were 33 differentially expressed miRNAs, of which 3 were significantly upregulated and the rest 30 were significantly downregulated. Target genes of these miRNAs were identified, and their functional enrichment was analyzed using gene ontology (GO) analysis. Importantly, target genes that can regulate heart rate and their paired upstream miRNAs attracted attention. Significant expression correlation between heart rate-related targets (Epas1, Bves, Hcn4, Cacna1e, Ank2, Slc8a1, Pde4d) and paired miRNAs (miR-142a-5p, miR-7b-5p, miR-144-3p, miR-34c-5p, miR-223-3p, miR-18a-5p) in mouse myocardial tissues was identified. MiR-142a-3p was downregulated in H9c2 cells and rat infarct tissues, and overexpressing miR-142a-3p restrains HO-induced H9c2 cell apoptosis. CONCLUSION:Cardioprotective miRNAs, such as miR-142a-3p, were identified in mouse myocardial tissues, and some specific miRNA-target pairs are associated with heart rate regulation.
10.1007/s12013-024-01528-x
Serum microRNA 143 and 223 Gene Expression Profiles as Potential Biomarkers in Individuals with Hepatitis and COVID-19.
Viruses
MicroRNAs (miRNAs) can act as biomarkers and descriptors of the association between infections and other diseases, such as hepatitis and COVID-19. This study aims to investigate the role of miRNA serum expression according to laboratory data concerning hepatitis and COVID-19. Seventy individuals recruited in Southern and Southeastern Brazil donated serum samples and were divided into four groups: (i) 20 negative subjects, (ii) 20 presenting hepatitis, (iii) 19 with COVID-19 and (iv) 11 with hepatitis and COVID-19. Three miRNAs (miR-122, miR-143 and miR-223) were evaluated using real-time PCR. Hematological and biochemical markers were also analyzed. MiR-143 and miR-223 were downregulated among the hepatitis/COVID-19 group ( < 0.05). A positive correlation was observed between miR-223 and lymphocytes. There was a negative correlation between alanine transaminase (ALT) and aspartate transaminase (AST) for miR-143 and miR-223 and gamma-glutamyl transferase (GGT), alkaline phosphatase (AP) and neutrophil/lymphocyte ratio (NLR) only for miR-223 ( < 0.05). For hepatic fibrosis (FIB-4), miR-122 and miR-143 had a greater association and miR-223 was more associated with a history of vaccination against COVID-19. MicroRNAs 143 and 223 could be useful as biomarkers for hepatitis coinfection with COVID-19.
10.3390/v16111734