Abstract
MiRNAs are a class of endogenous, short, single-stranded, non-coding RNAs, which are tightly linked to cardiac disorders such as myocardial ischemia/reperfusion (I/R) injury. MiR-34a is known to be involved in the hypoxia-induced cardiomyocytes apoptosis. However, the molecular mechanisms are unclear. In the present study, we demonstrate that under low glucose supply, rat cardiomyocytes are susceptible to hypoxia. Under short-time hypoxia, cellular glucose uptake and lactate product are induced but under long-time hypoxia, the cellular glucose metabolism is suppressed. Interestingly, an adaptive up-regulation of miR-34a by long-time hypoxia was observed both in vitro and in vivo, leading to suppression of glycolysis in cardiomyocytes. We identified lactate dehydrogenase-A (LDHA) as a direct target of miR-34a, which binds to the 3′-UTR region of LDHA mRNA in cardiomyocytes. Moreover, inhibition of miR-34a attenuated hypoxia-induced cardiomyocytes dysfunction through restoration of glycolysis. The present study illustrates roles of miR-34a in the hypoxia-induced cardiomyocytes dysfunction and proposes restoration of glycolysis of dysfunctional cardiomyocytes by inhibiting miR-34a during I/R might be an effectively therapeutic approach against I/R injury.
Highlights
During myocardial infarction, ischemia and/or reperfusion is the major cause of cardiomyocyte dysfunction, leading to worldwide morbidity and mortality [1]
Hypoxia is a major factor for the ischemia and/or reperfusion induced cardiomyocyte apoptosis during myocardial infarction [21]
We started to test the effects of hypoxia and/or low glucose on the cardiomyocytes survival
Summary
Ischemia and/or reperfusion is the major cause of cardiomyocyte dysfunction, leading to worldwide morbidity and mortality [1]. Low oxygen halts oxidative phosphorylation, leading to mitochondrial dysfunction, ATP depletion, and inhibition of myocardial contractile function [4]. Recent publications reported that miRNAs play important roles during myocardial infarction [8], ischemia/reperfusion (I/R) [9], and arrhythmia [10]. A recent study revealed that under cardiomyocyte hypoxia/reoxygenation (H/R) injury, alterations in miRNAs expression occur, leading to disturbances in downstream apoptotic pathway regulation [11]. It been known that down-regulation of miR-34a could reduce myocardial I/R injury by inhibiting cardiomyocyte apoptosis through targetting BCL-2 [13], suggesting a protective role of miR-34a during heart ischemia stress.
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