Time-dependent and ethanol-induced cardiac protection from ischemia mediated by mitochondrial translocation of varepsilonPKC and activation of aldehyde dehydrogenase 2.
Time-dependent and ethanol-induced cardiac protection from ischemia mediated by mitochondrial translocation of varepsilonPKC and activation of aldehyde dehydrogenase 2.
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DOI：
10.1016/j.yjmcc.2008.09.713
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发表时间：
2009-02
影响因子：
5
通讯作者：
Mochly-Rosen, Daria
中科院分区：
文献类型：
--
作者：
Churchill, Eric N.;Disatnik, Marie-Helene;Mochly-Rosen, Daria
关键词：
适量饮酒的心脏保护作用已在动物模型和人类中得到充分证明。对缺血和再灌注损伤（I/R）的保护作用是通过一种缺血预处理样机制进行的，该机制涉及到β蛋白激酶C（εPKC）的激活，并且依赖于乙醇处理的时间和持续时间。然而，εPKC的底物和该酶保护心脏免受I/R诱导的氧化损伤的分子机制尚未完全描述。使用体内急性心肌梗死的开胸模型，我们发现在短暂结扎冠状动脉左前降支30分钟之前60分钟（而不是之前15分钟）腹腔内注射乙醇（0.5 g/kg）可使I/R介导的损伤减少57%（测量为肌酸磷酸激酶释放到血液中的减少）。只有在心脏保护条件下，乙醇处理导致εPKC易位到心脏线粒体，在那里酶结合醛脱氢酶-2（ALDH 2）。ALDH 2是参与有毒醛如4-羟基-2-壬烯醛（4-HNE）的解毒的线粒体内酶，并且4-HNE至少部分地通过共价修饰和失活蛋白质（通过形成4-HNE加合物）介导氧化损伤。在心脏进行I/R后，乙醇处理，4-HNE蛋白加合物的水平较低，JNK 1/2和ERK 1/2的活动减少相对于心脏进行I/R在乙醇的情况下。总之，这项工作提供了一个洞察乙醇诱导的和ε PKC介导的保护心肌缺血，在体内心脏依赖性的基础。
The cardioprotective effects of moderate alcohol consumption have been well documented in animal models and in humans. Protection afforded against ischemia and reperfusion injury (I/R) proceeds through an ischemic preconditioning-like mechanism involving the activation of epsilon protein kinase C (εPKC) and is dependent on the time and duration of ethanol treatment. However, the substrates of εPKC and the molecular mechanisms by which the enzyme protects the heart from oxidative damage induced by I/R are not fully described. Using an open-chest model of acute myocardial infarction in vivo, we find that intraperitoneal injection of ethanol (0.5 g/kg) 60 minutes prior to (but not 15 minutes prior to) a 30-minute transient ligation of the left anterior descending coronary artery reduced I/R-mediated injury by 57% (measured as a decrease of creatine phosphokinase release into the blood). Only under cardioprotective conditions, ethanol treatment resulted in the translocation of εPKC to cardiac mitochondria, where the enzyme bound aldehyde dehydrogenase-2 (ALDH2). ALDH2 is an intra-mitochondrial enzyme involved in the detoxification of toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE) and 4-HNE mediates oxidative damage, at least in part, by covalently modifying and inactivating proteins (by forming 4-HNE adducts). In hearts subjected to I/R after ethanol treatment, the levels of 4-HNE protein adducts were lower and JNK1/2 and ERK1/2 activities were diminished relative to the hearts from rats subjected to I/R in the absence of ethanol. Together, this work provides an insight into the mitochondrial-dependent basis of ethanol-induced and εPKC-mediated protection from cardiac ischemia, in vivo.
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影响因子：
3.9
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