MiR-15b Is Implicated In Regulating Myocardial Reperfusion Injury By Promoting Apoptosis

Background: The most effective treatment for acute myocardial infarction(AMI) is reperfusion therapy, however, which may induce secondary damage tothe ischemic myocardium. The apoptosis of majority cardiomyocytes wasregulated via mitochondrial signaling pathway, which was mainly controlled byBcl-2family. Anti-apoptosis therapy can significantly decrease the infarct size.MiRNAs are a class of small endogeneous non-coding single-strand RNAs thatnegatively regulate gene expression at the post-transcriptional level by eitherdegrade or translational repress the target mRNAs. Non-cardiomyocytes studiessuggest that miR-15family members are strong apoptosis regulators, especiallymiR-15a/16-1and miR-15b/16-2clusters.Aims: Myocardial ischemia reperfusion (I/R) could induce altered expressionof microRNAs (miRNAs), which served as powerful regulators of geneexpression. Non-cardiomyocyte studies have indicated that miR-15a, miR-15band miR-16have a potential relationship with apoptosis. The present study wasaimed to reveal the roles of above miRNAs for the first time in myocardial I/Rinjury induced apoptosis.Methods and Results: Quantitative real time-PCR data showed that theexpression of miR-15a and miR-15b was upregulated in C57BL/6mice heartsubjected to I/R (n=7) while miR-16without any change, especially miR-15bshowed an increase in expression>3-fold. And the data was consistent withcardiomyocytes exposed to hypoxia/reoxygenation (H/R)(n=3). Recombinantadenoviral vectors were constructed to explore the functional role of miR-15b incultured cardiomyocytes exposed to H/R. Overexpression of miR-15b enhancedcell apoptosis and the loss of mitochondrial membrane potential (Δψm) determinedby flow cytometry analysis. Conversely, downexpression was cytoprotective.Furthermore, the inhibition of miR-15b increased the expression of Bcl-2protein,suppressed the release of mitochondrial cytochrome c (Cyt-c) to cytosol anddecreased the activity of caspase-3and caspase-9. Conclusion: MiR-15b may be the upstream regulator of mitochondrialsignaling pathway of I/R induced apoptosis by targeting Bcl-2.