Abstract
MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, has been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia/reperfusion induced cardiac injury. Here, we report microRNA-145, a tumor suppressor miRNA, can protect cardiomyocytes from hydrogen peroxide (H2O2)-induced apoptosis through targeting the mitochondrial pathway. Quantitative real-time PCR (qPCR) demonstrated that the expression of miR-145 in either ischemia/reperfused mice myocardial tissues or H2O2-treated neonatal rat ventricle myocytes (NRVMs) was markedly down-regulated. Over-expression of miR-145 significantly inhibited the H2O2-induced cellular apoptosis, ROS production, mitochondrial structure disruption as well as the activation of key signaling proteins in mitochondrial apoptotic pathway. These protective effects of miR-145 were abrogated by over-expression of Bnip3, an initiation factor of the mitochondrial apoptotic pathway in cardiomyocytes. Finally, we utilized both luciferase reporter assay and western blot analysis to identify Bnip3 as a direct target of miR-145. Our results suggest miR-145 plays an important role in regulating mitochondrial apoptotic pathway in heart challenged with oxidative stress. MiR-145 may represent a potential therapeutic target for treatment of oxidative stress-associated cardiovascular diseases, such as myocardial ischemia/reperfusion injury.
Highlights
Myocardial infarction is one of the leading causes of morbidity and mortality worldwide
To determine whether miR-145 plays a role in the regulation of H2O2-induced apoptosis in cardiomyocytes, we performed the adenovirus-mediated over-expression of miR-145
MiR-145 significantly lowered the apoptosis rate in the existence of Bcl2/adenovirus E1B kDa-interacting protein 3 (Bnip3) coding sequence (CDS)/39UTR, but had mild effect in the existence of Bnip3 CDS. These results suggest that miR-145 plays a protective role against the oxidative stress-induced cardiomyocyte apoptosis and this regulation of miR-145 is linked with Bnip3
Summary
Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Despite of the essential role of the mitochondrial pathway in oxidative stress-mediated cardiomyocyte apoptosis, how this pathway is regulated at different levels remains elusive. MiRNA, a class of small, non-encoding RNAs that transcriptionally or posttranscriptionally modulate the expression of their target genes, has been implicated as regulatory molecules in many cardiovascular diseases, including myocardial ischemia-reperfusion injury [5,6]. MiR-145 is a tumor suppressor miRNA that has been recently implicated in the regulation of apoptosis networks in tumor cells through its ability of targeting various anti-apoptotic molecules [7,8,9]. Little is known about whether miR-145 is associated with cardiomyocyte apoptosis under oxidative stress or how it interferes with the mitochondrial apoptotic pathway
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