Abstract
Aims. miR-208a is associated with adverse outcomes in several cardiac pathologies known to have increased apoptosis, including myocardial infarction (MI). We investigated if miR-208a has proapoptotic effects on ischemic cardiomyocytes and if its silencing has therapeutic benefits in MI. Methods and Results. The effect of miR-208a on apoptosis during ischemia was studied in cultured neonatal mice myocytes transfected with agomir or antagomir. Differential gene expression was assessed using microarrays. MI was induced in male C57BL/6 mice randomly assigned to antagomir (n = 6) or control group (n = 7), while sham group (n = 7) had sham operation done. Antagomir group received miR208a antagomir, while control and sham group mice received vehicle only. At 7 and 28 days, echocardiography was done and thereafter hearts were harvested for analysis of apoptosis by TUNEL method, fibrosis using Masson's trichrome, and hypertrophy using hematoxylin and eosin. miR-208a altered apoptosis genes expression and increased apoptosis in ischemic cardiomyocytes. Therapeutic inhibition of miR-208a decreased cardiac fibrosis, hypertrophy, and apoptosis and significantly improved cardiac function 28 days after MI. Conclusion. miR-208a alters apoptosis genes expression and promotes apoptosis in ischemic cardiomyocytes, and its silencing attenuates apoptosis, fibrosis, and hypertrophy after MI, with significant improvement in cardiac function.
Highlights
Apoptosis, a distinct form of cell death, is at the heart of both mechanical and molecular mechanisms of cardiomyocyte loss during ischemia
MicroRNAs are small noncoding ribonucleic acids (RNAs) measuring 18–25 nucleotides that are involved in posttranscription regulation of gene expression [4, 5]. miR208a is a cardiac specific microRNA coded for in an intron of myosin heavy chain 6 (Myh6) gene and regulates cardiac conduction, stress response, and gene expression [6,7,8,9]
We investigated the role of miR-208a in cardiomyocyte apoptosis in an ischemic setting
Summary
A distinct form of cell death, is at the heart of both mechanical and molecular mechanisms of cardiomyocyte loss during ischemia. After MI, there is heightened apoptosis in the peri-infarct and noninfarcted myocardium, and this coincides with increased left ventricular diameter and decreased cardiac function [1]. To this effect, therapies that inhibit apoptosis in MI have been shown to improve cardiac function [2, 3]. No study as yet has been done to investigate its role in cardiomyocyte apoptosis despite these cardiac pathologies being associated with increased myocyte apoptosis. We investigated the effect of miR-208a on cardiomyocyte apoptosis and apoptosis related genes and if its silencing has any therapeutic benefit in myocardial infarction. To the best of our knowledge, our study is the first to explore the antiapoptotic effects of miR-208a silencing and the therapeutic benefits of miR-208a antagomir in myocardial infarction
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