Abstract
Myocardial ischemia-reperfusion (I-R) injury lacks effective treatments. The miR-17-92 cluster plays important roles in regulating proliferation, apoptosis, cell cycle and other pivotal processes. However, their roles in myocardial I-R injury are largely unknown. In this study, we found that miR-19b was the only member of the miR-17-92 cluster that was downregulated in infarct area of heart samples from a murine model of I-R injury. Meanwhile, downregulation of miR-19b was also detected in H2O2-treated H9C2 cells in vitro mimicking oxidative stress occurring during myocardial I-R injury. Using flow cytometry and Western blot analysis, we found that overexpression of miR-19b decreased H2O2-induced apoptosis and improved cell survival, while downregulation of that had inverse effects. Furthermore, PTEN was negatively regulated by miR-19b at the protein level while silencing PTEN could completely block the aggravated impact of miR-19b inhibitor on H2O2-induced apoptosis in H9C2 cardiomyocytes, indicating PTEN as a downstream target of miR-19b controlling H2O2-induced apoptosis. These data indicate that miR-19b overexpression might be a novel therapy for myocardial I-R injury.
Highlights
Acute myocardial infarction represents one of the leading causes of morbidity and mortality worldwide [1]
Using Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), miR-19b was found to be the only one in the miR-17-92 cluster that was downregulated in infarct area of heart samples from a murine model of I-R injury (Figure 1B)
We found that H2O2 treatment for 2 h significantly increased apoptosis in H9C2 cardiomyocytes as analyzed by flow cytometry (Figure 2A) and western blot analysis for Bcl-2, Bax and cleaved-Caspase 3 to Caspase 3 ratio (Figure 2B)
Summary
Acute myocardial infarction represents one of the leading causes of morbidity and mortality worldwide [1]. Timely reperfusion of the myocardium can limit the infarct area and improve long term cardiac function and survival of the patients, reperfusion itself can lead to myocardial injury [2, 3]. Accumulating evidence show that miRNA dysregulation contributes to multiple cardiovascular diseases including ischemia-reperfusion (I-R) injury [7,8,9,10,11]. MiR-1, -26, -29, -21, -24, -103, -133, and -210 have been reported to be regulators of I-R injury either in the early or in the late stage after myocardial infarction, though the underlying mechanisms are largely unclarified [12, 13]. Dysregulated miR-17-92 cluster has been reported in cardiovascular, immune and neurodegenerative diseases [14]. The roles of miR-17-92 in cardiac development, cardiomyocyte proliferation, and cardiac ageing have been reported [14-
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