Zhu Rui-Yao, Zhang Di, Zou Han-Dong, Zuo Xiao-Shu, Zhou Qing-Shan, Huang He
Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Cardiology, No. 99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, Hubei Province, People's Republic of China.
In Vitro Cell Dev Biol Anim. 2016 Dec;52(10):1020-1025. doi: 10.1007/s11626-016-0065-6. Epub 2016 Jun 23.
MicroRNAs play critical roles in regulating cell survival under multiple pathological conditions of heart diseases. Oxidative stress-induced apoptosis contributes greatly to heart ischemia-reperfusion injury. Herein, we describe a novel regulatory role of miR-28 on the survival of cardiomyocytes. We show that miR-28 was upregulated in cardiomyocytes treated with hydrogen peroxide (HO). MiR-28 gain of function sensitized cell apoptosis, whereas miR-28 loss of function partially rescued cell apoptosis induced by HO. Importantly, we observed a significant reduction in Akt/mammalian target of rapamycin (mTOR) signaling activity after miR-28 treatment. Luciferase activity assay and western blot analysis both revealed that, phosphoinositide-dependent kinase-1 (PDK1), which is critical for Akt activation, was directly and negatively modulated by miR-28. Our results therefore indicate that miR-28 regulates oxidative stress-induced cell apoptosis in heart muscle cells, which possibly involves a PDK1/Akt/mTOR-dependent mechanism. MIR-28 could serve as a critical therapeutic target to diminish oxidative stress-induced cell death in the heart.
微小RNA在多种心脏病病理状态下调节细胞存活中发挥关键作用。氧化应激诱导的细胞凋亡在心脏缺血再灌注损伤中起很大作用。在此，我们描述了miR-28对心肌细胞存活的一种新的调节作用。我们发现，在用过氧化氢（HO）处理的心肌细胞中miR-28上调。miR-28功能增强使细胞凋亡敏感化，而miR-28功能缺失部分挽救了由HO诱导的细胞凋亡。重要的是，我们观察到miR-28处理后Akt/雷帕霉素哺乳动物靶蛋白（mTOR）信号活性显著降低。荧光素酶活性测定和蛋白质印迹分析均显示，对Akt激活至关重要的磷酸肌醇依赖性激酶-1（PDK1）受到miR-28的直接负调控。因此，我们的结果表明，miR-28调节心肌细胞中氧化应激诱导的细胞凋亡，这可能涉及一种PDK1/Akt/mTOR依赖性机制。MIR-28可作为减轻心脏氧化应激诱导的细胞死亡的关键治疗靶点。
