Mitophagy Is Required for Acute Cardioprotection by Simvastatin
Mitophagy Is Required for Acute Cardioprotection by Simvastatin
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DOI：
10.1089/ars.2013.5416
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发表时间：
2014-11-10
影响因子：
6.6
通讯作者：
Gottlieb, Roberta A.
中科院分区：
文献类型：
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作者：
Andres, Allen M.;Hernandez, Genaro;Gottlieb, Roberta A.
目的：我们已经证明自噬和有丝自噬是预处理所必需的。虽然他汀类药物的心脏保护作用是众所周知的，但自噬/线粒体自噬在他汀类药物介导的心脏保护中的作用尚不清楚。在本研究中，我们使用HL-1心肌细胞和缺血/再灌注小鼠来阐明他汀类药物介导的心脏保护机制。结果：暴露于辛伐他汀24小时的HL-1心肌细胞表现出蛋白激酶B (Akt)/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路降低，unc-51样激酶1激活增加，自噬和有丝分裂上调。在给予辛伐他汀的小鼠心脏中也得到了类似的结果。甲羟戊酸钠可消除辛伐他汀对HL-1细胞Akt/mTOR信号传导和自噬诱导的影响，表明其作用是通过抑制3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）还原酶介导的。辛伐他汀处理的HL-1细胞表现出Parkin和p62/SQSTM1的线粒体易位、分裂和线粒体自噬。由于Parkin是线粒体自噬所必需的，并且在心脏中表达，我们研究了辛伐他汀对Parkin基因敲除小鼠梗死面积的影响。辛伐他汀在野生型小鼠中减少了梗死面积，但在帕金基因敲除小鼠中没有显示出益处。抑制HMG-CoA还原酶限制了甲羟戊酸在胆固醇和辅酶Q(10) （CoQ）生物合成中的可用性。补充CoQ对HL-1细胞中他汀类药物诱导的Akt/mTOR去磷酸化或巨噬无影响，但可有效阻断有丝分裂。重要的是，补充CoQ在体内消除了他汀介导的心脏保护。创新与结论：急性辛伐他汀治疗可抑制mTOR信号传导并触发帕金森依赖性线粒体自噬，后者是保护心脏所必需的。CoQ与辛伐他汀联合使用会损害线粒体自噬和心脏保护作用。这些结果引起了人们的关注，即CoQ可能会干扰他汀类药物通过刺激线粒体自噬介导的抗缺血益处。Antioxid。氧化还原信号，21,1960-1973。
Aims: We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. Results: HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q(10) (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Innovation and Conclusion: Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy. Antioxid. Redox Signal. 21, 1960-1973.