Activation of aldehyde dehydrogenase 2 (ALDH2) confers cardioprotection in protein kinase C epsilon (PKCvarepsilon) knockout mice.
Activation of aldehyde dehydrogenase 2 (ALDH2) confers cardioprotection in protein kinase C epsilon (PKCvarepsilon) knockout mice.
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DOI：
10.1016/j.yjmcc.2009.10.030
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发表时间：
2010-04
影响因子：
5
通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
--
作者：
Budas GR;Disatnik MH;Chen CH;Mochly-Rosen D
急性给药乙醇可减轻心脏缺血再灌注损伤。已有研究表明，乙醇对心肌的急性细胞保护作用是通过PKCε激酶介导的。我们最近发现醛脱氢酶2 （ALDH2）是PKCε的底物，其激活对体内心脏保护是必要和充分的。ALDH2代谢细胞毒性活性醛，如4-羟基-2-壬烯醛（4-HNE），这些醛在心脏缺血/再灌注过程中积累。在这里，我们使用PKCε敲除小鼠和ALDH2的直接激活剂Alda-44的组合来进一步研究PKCε和ALDH2在心脏保护中的相互作用。我们报道，乙醇预处理需要PKCε，而在野生型和PKCε敲除的心脏中，直接激活ALDH2可减少梗死面积。我们的数据表明，在乙醇预处理中，ALDH2位于PKCε的下游，直接激活ALDH2可以绕过PKCε诱导细胞保护的需要。我们还报道，除了激活ALDH2外，Alda-44还通过减少4-HNE-ALDH2蛋白加合物的形成来阻止4-HNE诱导的ALDH2失活。因此，Alda-44促进了在缺血心肌中积累的细胞毒性活性醛的代谢。综上所述，我们的研究结果表明，直接激活ALDH2可能代表了一种利用乙醇的心脏保护作用而没有与饮酒相关的副作用的方法。
Acute administration of ethanol can reduce cardiac ischemia/reperfusion injury. Previous studies demonstrated that the acute cytoprotective effect of ethanol on the myocardium is mediated by protein kinase C epsilon (PKCε). We recently identified aldehyde dehydrogenase 2 (ALDH2) as an PKCε substrate, whose activation is necessary and sufficient to confer cardioprotection in vivo. ALDH2 metabolizes cytotoxic reactive aldehydes, such as 4-hydroxy-2-nonenal (4-HNE), which accumulate during cardiac ischemia/reperfusion. Here, we used a combination of PKCε knockout mice and a direct activator of ALDH2, Alda-44, to further investigate the interplay between PKCε and ALDH2 in cardioprotection. We report that ethanol preconditioning requires PKCε, whereas direct activation of ALDH2 reduces infarct size in both wild type and PKCε knockout hearts. Our data suggest that ALDH2 is downstream of PKCε in ethanol preconditioning and that direct activation of ALDH2 can circumvent the requirement of PKCε to induce cytoprotection. We also report that in addition to ALDH2 activation, Alda-44 prevents 4-HNE induced inactivation of ALDH2 by reducing the formation of 4-HNE-ALDH2 protein adducts. Thus, Alda-44 promotes metabolism of cytotoxic reactive aldehydes that accumulate in ischemic myocardium. Taken together, our findings suggest that direct activation of ALDH2 may represent a method of harnessing the cardioprotective effect of ethanol without the side effects associated with alcohol consumption.
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影响因子：
4.1
作者：
Doorn, JA;Hurley, TD;Petersen, DR
通讯作者：
Petersen, DR
影响因子：
5
作者：
Churchill, Eric N.;Disatnik, Marie-Helene;Mochly-Rosen, Daria
通讯作者：
Mochly-Rosen, Daria
DOI：
10.1073/pnas.0503723102
发表时间：
2005-08-23
影响因子：
11.1
作者：
Chen, ZQ;Foster, MW;Stamler, JS
通讯作者：
Stamler, JS
影响因子：
5
作者：
Chen, CH;Mochly-Rosen, D
通讯作者：
Mochly-Rosen, D
影响因子：
4.7
作者：
Camandola, S;Poli, G;Mattson, MP
通讯作者：
Mattson, MP