MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury.
MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury.
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DOI：
10.1161/circulationaha.110.964684
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发表时间：
2010-09-28
期刊：
影响因子：
37.8
通讯作者：
Fan GC
中科院分区：
文献类型：
--
作者：
Wang X;Zhang X;Ren XP;Chen J;Liu H;Yang J;Medvedovic M;Hu Z;Fan GC
microRNAs (miRs) participate in many cardiac pathophysiological processes including ischemia/reperfusion (I/R)-induced cardiac injury. Recently, we and others observed that miR-494 was downregulated in murine I/R injured and human infarcted hearts. However, the functional consequence of miR-494 in response to I/R remains unknown. We generated a mouse model with cardiac-specific overexpression of miR-494. Transgenic (TG) hearts and wild-type (WT) hearts from multiple lines were subjected to global no-flow I/R using the Langendorff system. TG hearts exhibited improved recovery of contractile performance over the reperfusion period. This improvement was accompanied by remarkable decreases in both lactate dehydrogenase release and the extent of apoptosis in TGs, compared to WTs. Also, myocardial infarction size was significantly reduced in TGs upon I/R in vivo, versus WTs. Similarly, acute overexpression of miR-494 in cultured adult cardiomyocytes demonstrated an inhibition of caspase-3 activity and reduced cell death upon simulated I/R. In vivo treatment with antagomiR-494 increased I/R-triggered cardiac injury relative to the administration of mutant antagomiR-494 and saline controls. We further identified that three pro-apoptotic proteins (PTEN, ROCK1 and CaMKIIδ) and two anti-apoptotic proteins (FGFR2 and LIF) were authentic targets for miR-494. Importantly, the Akt-mitochondrial signaling pathway was activated in miR-494-overexpressing myocytes. Our findings suggest that although miR-494 targets both pro-apoptotic and anti-apoptotic proteins, the ultimate consequence is activation of the Akt pathway, leading to cardioprotective effects against I/R-induced injury. Thus, miR-494 may constitute a new therapeutic agent for the treatment of ischemic heart disease.
