Sandip Chaugai

Plasma microRNA-133a is a new marker for both acute myocardial infarction and underlying coronary artery stenosis

BackgroundPrevious study demonstrated that miR-133a was released into blood from injured myocardium in cardiovascular diseases. However, the dynamic change of circulating miR-133a level in the early phase of acute myocardial infarction (AMI) and the correlation between miR-133a and severity of coronary stenosis in coronary heart disease (CHD) patients are not clear.Methods and resultsThree different cohorts (including 13 AMI patients, 176 angina pectoris patients and 127 control subjects) were enrolled to investigate the expression levels of circulating miR-133a in patients with myocardial ischemia and also the relationship between plasma miR-133a and severity of coronary stenosis. Plasma miR-133a levels of participants were examined by real-time quantitative PCR. Simultaneously, plasma cardiac troponin I (cTnI) concentrations were measured by ELISA assays. The results showed that circulating miR-133a level was significantly increased in AMI patients in time-dependent manner, and achieved a 72.1 fold peak at 21.6u2009±u20094.5xa0hours after the onset of AMI symptoms and exhibited a similar trend to plasma cTnI level. We also found that plasma miR-133a levels were higher in CHD patients than control group. Importantly, the levels of circulating miR-133a positively correlated with the severities of the coronary artery stenosis. Receiver operating characteristic (ROC) analysis revealed that circulating miR-133a had considerable diagnostic accuracy for CHD with an AUC of 0.918 (95% confidence interval 0.877-0.960).ConclusionsCirculating miR-133a may be a new biomarker for AMI and as a potential diagnostic tool. And increased miR-133a level may be used to predict both the presence and severity of coronary lesions in CHD patients.

MicroRNA‐214 Is Upregulated in Heart Failure Patients and Suppresses XBP1‐Mediated Endothelial Cells Angiogenesis

More and more miRNAs have been shown to regulate gene expression in the heart and dysregulation of their expression has been linked to cardiovascular diseases including the miR‐199a/214 cluster. However, the signature of circulating miR‐214 expression and its possible roles during the development of heart failure has been less well studied. In this study, we elucidated the biological and clinical significance of miR‐214 dysregulation in heart failure. Firstly, circulating miR‐214 was measured by quantitative PCR, and we found that miR‐214 was upregulated in the serum of chronic heart failure patients, as well as in hypertrophic and failing hearts of humans and mice. Adeno‐associated virus serotype 9 (AAV9)‐mediated miR‐214 silencing attenuates isoproterenol (ISO) infusion‐induced cardiac dysfunction and impairment of cardiac angiogenesis in mice. Mechanistically, miR‐214 overexpression reduces angiogenesis of HUVECs by targeting XBP1, an important transcription factor of unfolded protein response, and XBP1 silencing decreases HUVECs proliferation and angiogenesis similar to miR‐214 overexpression. Furthermore, ectopic expression of XBP1 enhances endothelial cells proliferation and tube formation, and reverses anti‐angiogenic effect of miR‐214 over expression. All these findings suggest that miR‐214 is an important regulator of angiogenesis in heart in vitro and in vivo, likely via regulating the expression of XBP1, and demonstrate that miR‐214 plays an essential role in the control/inhibition of cardiac angiogenesis. J. Cell. Physiol. 230: 1964–1973, 2015.

miR-21-3p Regulates Cardiac Hypertrophic Response by Targeting Histone Deacetylase-8

AIMSnGrowing evidences indicate that microRNAs (miRNAs) are involved in cardiac hypertrophy development. Multiple miRNAs have been identified as diagnostic and prognostic biomarkers of cardiac hypertrophy, as well as potential therapeutic tools. The present study aimed to investigate the functions and regulatory mechanisms of miR-21-3p in cardiac hypertrophy.nnnMETHODS AND RESULTSnDecreased expression of miR-21-3p was observed in cardiac hypertrophy induced by transverse aortic constriction (TAC) and angiotensin (Ang) II infusion in mice. To further explore the role of miR-21-3p in cardiac hypertrophy, rAAV-miR-21-3p was administered intravenously in mice. Overexpression of miR-21-3p markedly suppressed TAC-induced cardiac hypertrophy and also blocked Ang II-induced cardiac hypertrophy as determined by cardiac function measurement and biomarker detection. Furthermore, western blot assays showed that histone deacetylase-8 (HDAC8) was silenced by miR-21-3p, and luciferase reporter assays showed that miR-21-3p binds to the 3 UTR of HDAC8. Moreover, re-expression of HDAC8 attenuated miR-21-3p-mediated suppression of cardiac hypertrophy by enhancing phospho-Akt and phospho-Gsk3β expression.nnnCONCLUSIONnOur data reveal a role of miR-21-3p in regulating HDAC8 expression and Akt/Gsk3β pathway, and suggest that modulation of miR-21-3p levels may provide a therapeutic approach for cardiac hypertrophy.

Atherosclerosis-Related Circulating miRNAs as Novel and Sensitive Predictors for Acute Myocardial Infarction

Background The dysregulated expressions of circulating miRNAs have been detected in various cardiovascular diseases. In our previous experiments, the altered expressions of circulating miRNA-21-5p, miRNA-361-5p and miRNA-519e-5p were confirmed in patients with coronary atherosclerosis by miRNA microarrays. However, the expression levels of these circulating miRNAs in the early phase of acute myocardial infarction (AMI) are still unknown. In the present study, our aims were to examine the expressions of circulating miR-21-5p, miR-361-5p and miR-519e-5p in AMI patients, and assess their clinical applications for diagnosing and monitoring AMI. Results Two different cohorts were enrolled in this study. The first cohort included 17 AMI patients and 28 healthy volunteers, and the second cohort included 9 AMI patients, 9 ischemic stroke patients, 8 patients with pulmonary embolism, and 12 healthy volunteers. Quantitative real-time PCR and ELISA assays were preformed to detect the concentrations of plasma miRNAs and cardiac troponin I (cTnI), respectively. The results showed that the plasma levels of miR-21-5p and miR-361-5p were significantly increased in AMI patients, whereas the concentration of circulating miR-519e-5p was reduced. Interestingly, the levels of these circulating miRNAs correlated with the concentrations of plasma cTnI. Receiver operating characteristic (ROC) analysis revealed that these three circulating miRNAs had considerable diagnostic accuracy for AMI with high values of area under ROC curve (AUC). Importantly, combining the three miRNAs significantly increased the diagnostic accuracy. Furthermore, cell experiments demonstrated that these plasma miRNAs may originate from injured cardiomyocytes induced by hypoxia. In addition, the levels of all the three circulating miRNAs in ischemic stroke (IS) and pulmonary embolism (PE) were elevated, whereas the decreased level of plasma miR-519e-5p was only detected in AMI. ROC analysis demonstrated that circulating miR-519e-5p may be a useful biomarker for distinguishing AMI from other ischemic diseases. Conclusions Circulating miRNAs may be novel and powerful biomarkers for AMI and they could be potential diagnostic tool for AMI.

Meta-analysis of Hsa-mir-499 polymorphism (rs3746444) for cancer risk: evidence from 31 case-control studies

BackgroundMicroRNAs (miRNAs) are a family of endogenous, small and non-coding RNAs that regulate gene expression negatively at the post-transcriptional level by suppressing translation or degrading target mRNAs, and are involved in diverse biological and pathological processes. Single nucleotide polymorphisms (SNPs) which are located in the miRNA-coding genes may participate in the process of development and diseases by altering the expression of mature miRNA. Recent studies investigating the association between hsa-mir-499 polymorphism (rs3746444) and cancer risk have yielded conflicting results.MethodsIn this meta-analysis, we conducted a search of case–control studies on the associations of SNP rs3746444 with susceptibility to cancer in electronic databases. A total of 31 studies involving 12799 cases and 14507 controls were retrieved and the strength of the association was estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in controls. Subgroup analyses were done by racial descent and cancer type. Publication bias of literatures was evaluated by visual inspection of funnel plots and the linear regression asymmetry test by Egger et al. Sensitivity analysis was conducted by excluding one study at a time to examine the influence of individual data set on the pooled ORs.ResultsOverall, significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models. In the stratified analyses, increased risks were found in Asians, but not in Caucasians in all comparison models tested. Moreover, significant association with an increased risk was found in Chinese population. Also, much higher significant association with increased cancer risks were found in Iranian population. In different cancer types, a decreased risk was found in esophageal cancer.ConclusionOur meta-analysis suggested that hsa-mir-499 rs3746444 Tu2009>u2009C polymorphism is associated with the risk of cancer in Asians, mainly in Iranian and Chinese population. However, rs3746444 Tu2009>u2009C polymorphism is negatively associated with the risk of esophageal cancer.

Chronic inhibition of cyclic guanosine monophosphate-specific phosphodiesterase 5 prevented cardiac fibrosis through inhibition of transforming growth factor β-induced Smad signaling

Recent evidences suggested that cyclic guanosine monophosphate-specific phosphodiesterase 5 (PDE5) inhibitor represents an important therapeutic target for cardiovascular diseases. Whether and how it ameliorates cardiac fibrosis, a major cause of diastolic dysfunction and heart failure, is unknown. The purpose of this study was to investigate the effects of PDE5 inhibitor on cardiac fibrosis. We assessed cardiac fibrosis and pathology in mice subjected to transverse aortic constriction (TAC). Oral sildenafil, a PDE5 inhibitor, was administered in the therapy group. In control mice, 4 weeks of TAC induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation (proliferation and transformation to myofibroblasts). Sildenafil treatment markedly prevented TAC-induced cardiac dysfunction, cardiac fibrosis and cardiac fibroblast activation but did not block TAC-induced transforming growth factor-β1 (TGF-β1) production and phosphorylation of Smad2/3. In isolated cardiac fibroblasts, sildenafil blocked TGF-β1-induced cardiac fibroblast transformation, proliferation and collagen synthesis. Furthermore, we found that sildenafil induced phosphorylated cAMP response element binding protein (CREB) and reduced CREB-binding protein 1 (CBP1) recruitment to Smad transcriptional complexes. PDE5 inhibition prevents cardiac fibrosis by reducing CBP1 recruitment to Smad transcriptional complexes through CREB activation in cardiac fibroblasts.

Trimetazidine prevents macrophage‐mediated septic myocardial dysfunction via activation of the histone deacetylase sirtuin 1

Sepsis is a systemic inflammatory response accompanied by excessive production of inflammatory cytokines and cardiovascular dysfunction. Importantly, macrophage‐derived pro‐inflammatory agents play a key role in cardiovascular impairment in sepsis. Here we have investigated the effects of trimetazidine (TMZ) on pro‐inflammatory responses of macrophages in endotoxin‐induced myocardial dysfunction.

Cardioprotective Effect of Thiazide-Like Diuretics: A Meta-Analysis

BACKGROUND AND PURPOSEnThiazide diuretics (TD), including thiazide-type (chlorothiazide and hydrochlorothiazide) and thiazide-like diuretics (indapamide and chlorthalidone), have been used for the treatment of hypertension for more than 5 decades. This meta-analysis aimed to evaluate whether TD, including thiazide-type and thiazide-like diuretics have additional cardioprotective effects.nnnEXPERIMENTAL APPROACHnWe performed a pooled study of 19 randomized clinical trials (RCTs). PubMed and EMBASE databases were searched for RCTs assessing TD treatment in patients with hypertension.nnnKEY RESULTSnNineteen RCTs involving 112,113 patients (56,802 in TD; 55,311 in control) were included. The incidence ratio of cardiac events (CVs) was 34.3 vs. 37.8 per 1,000 patient-years in patients randomized to TD and controls, respectively. TD treatment was associated with reductions in the risks of CVs (odds ratio (OR): 0.86, P = 0.007) and heart failure (OR: 0.62, P < 0.001), but not different in stroke (OR: 0.92, P = 0.438) or CHD (OR: 0.95, P = 0.378) between diuretics and controls. Further analysis showed that the observed benefits were mainly confined to thiazide-like diuretic therapy rather than thiazide-type diuretics with a significant reduction in the risk of CVs (OR: 0.78, P < 0.001), heart failure (OR: 0.57, P < 0.001) and stroke (OR: 0.82, P = 0.016).nnnCONCLUSIONS AND IMPLICATIONSnThis study suggests that use of TD in hypertensive patients results in a reduction in the risk of CVs. Moreover, thiazide-like diuretics have greater protective effect against CVs than thiazide-type diuretics, especially on heart failure, suggesting that preferential use of thiazide-like diuretics over thiazide-type diuretics may result in greater cardiovascular benefits in hypertensive patients.

Effect of Nicorandil in Patients with Heart Failure: A Systematic Review and Meta-Analysis

BACKGROUND AND PURPOSEnIt is unclear whether nicorandil, a metabolic therapeutic drug, can be applied clinically to therapy of heart failure (HF). This meta-analysis evaluated therapeutic effects of nicorandil on HF patients.nnnEXPERIMENTAL APPROACHnWe performed a systematic review and meta-analysis of published studies evaluating effect of nicorandil on HF patients. Studies were stratified according to controlled versus uncontrolled designs and analyzed using random-effects meta-analysis models.nnnKEY RESULTSnWe identified a total of 20 studies with a total of 1222 patients. In five randomized controlled studies, nicorandil treatment resulted in reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, P < 0.001) and improved cardiac pump function (SMD: 0.31, P = 0.02). In 15 observational studies, nicorandil therapy increases cardiac pump function (SMD: 0.75, P < 0.001), improves NYHA functional class (WMD: -1.33, P < 0.001), decreases PCWP (WMD: -6.86 mm Hg, P < 0.001), and pulmonary arterial pressure (SMD: -0.84, P < 0.001).nnnCONCLUSIONS AND IMPLICATIONSnThe use of nicorandil in HF patients exerts substantial beneficial effects, suggesting that it may be an additional therapeutic agent for HF.

Trimetazidine prevents macrophage mediated septic myocardial dysfunction via Sirt1

Sepsis is a systemic inflammatory response accompanied by excessive production of inflammatory cytokines and cardiovascular dysfunction. Importantly, macrophage‐derived pro‐inflammatory agents play a key role in cardiovascular impairment in sepsis. Here we have investigated the effects of trimetazidine (TMZ) on pro‐inflammatory responses of macrophages in endotoxin‐induced myocardial dysfunction.