MicroRNA-200c exacerbates the ischemia/reperfusion injury of heart through targeting the glutaminase (GLS)-mediated glutamine metabolism

OBJECTIVE: Cardiac ischemia and reperfusion, the common pathophysiological processes during cardiovascular surgery, are followed by oxidative stresses during the restoration of blood flow to the tissue, known as ischemia/reperfusion (IR) injury. microRNAs (miRNAs) are a group of endogenous, short and noncoding RNAs that post-transcriptionally repress their target mRNA expressions. Currently, the roles of microRNAs in the IR are still under investigated. This study will investigate the roles and mechanisms of miRNAs in the ischemia/reperfusion injury of the heart.

MATERIALS AND METHODS: A rat myocardial ischemia-reperfusion injury model was established in this study. MiR-200c expression was measured by qRT-PCR. MiR-200c mimics was transfected into rat H9c2 cardiomyocytes to test the effects of miR-200c on the glutamine metabolism. The glutamine uptake, glutamine dehydrogenase activity, α-ketoglutarate, and glutaminase were assessed.

RESULTS: Here, we show that endogenous miR-200c expression is stimulated by IR in rat heart. We observed miR-200c expressions were induced by H2O2 treatments in H9c2 rat cardiomyocytes. Overexpression of miR-200c increased the ROS levels under H2O2. Moreover, the glutamine metabolism is suppressed by IR in rat heart. We identified miR-200c directly targets the glutaminase (GLS) through complimentary binding to the 3'UTR reagent of GLS. We report either knockdown of GLS by siRNA or overexpression of miR-200c suppresses glutamine metabolism in H9c2 cardiomyocytes. Notably, the miR-200c inhibitor-pretreated rat heart exhibits improved heart function in IR.

CONCLUSIONS: This study reports an important function of miR-200c in the regulation of glutamine metabolism during ischemia/reperfusion injury and will contribute to the development of new diagnostic and therapeutic interventions for the protection of IR.

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