Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases.
Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases.
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DOI：
10.1016/j.yjmcc.2010.03.017
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发表时间：
2010-08
影响因子：
5
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Ma H;Yu L;Byra EA;Hu N;Kitagawa K;Nakayama KI;Kawamoto T;Ren J
饮酒导致心肌收缩功能障碍，可能是由于乙醇及其主要代谢产物乙醛的毒性。本研究旨在探讨线粒体乙醛脱氢酶-2（ALDH 2）基因敲除（KO）对急性乙醇缺血诱导的心肌细胞功能障碍的影响。将野生型（WT）和ALDH 2 KO小鼠进行急性乙醇（3g/kg，i. p.）激发和心肌细胞收缩功能，24小时后使用IonOptix®边缘检测系统进行评估。Western blot分析ALDH 2、蛋白磷酸酶2A（PP 2A）、Akt磷酸化和糖原合成酶激酶-3 β（GSK-3β）。ALDH 2 KO加重乙醇诱导的心脏乙醛水平升高。乙醇暴露抑制心肌细胞收缩功能，包括细胞缩短幅度和最大缩短/再缩短速度降低，以及再缩短持续时间延长和响应于增加刺激频率的峰值缩短的更大下降，其作用被ALDH 2 KO显著夸大。ALDH 2 KO还揭示了乙醇诱导的缩短持续时间的延长。此外，ALDH抑制剂氰胺会加剧乙醇诱导的心肌细胞机械缺陷的短期体外孵育。乙醇处理抑制了与PP 2A上调相关的Akt和GSK-3β的磷酸化，这通过ALDH 2 KO增强。ALDH 2 KO加重乙醇诱导的线粒体膜电位下降。这些结果表明，ALDH 2缺乏导致乙醇诱导的心肌细胞功能恶化，可能是由于蛋白磷酸酶表达上调，Akt活化抑制，随后线粒体功能受损。这些发现描述了ALDH 2在酒精性心肌病发病机制中的关键作用。
Alcohol consumption leads to myocardial contractile dysfunction possibly due to the toxicity of ethanol and its major metabolite acetaldehyde. This study was designed to examine the influence of mitochondrial aldehyde dehydrogenase-2 (ALDH2) knockout (KO) on acute ethanol exposure-induced cardiomyocyte dysfunction. Wild-type (WT) and ALDH2 KO mice were subjected to acute ethanol (3 g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24 hrs later using an IonOptix® edge-detection system. Western blot analysis was performed to evaluate ALDH2, protein phosphatase 2A (PP2A), phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β). ALDH2 KO accentuated ethanol-induced elevation in cardiac acetaldehyde levels. Ethanol exposure depressed cardiomyocyte contractile function including decreased cell shortening amplitude and maximal velocity of shortening/relengthening as well as prolonged relengthening duration and a greater decline in peak shortening in response to increasing stimulus frequency, the effect of which was significantly exaggerated by ALDH2 KO. ALDH2 KO also unmasked an ethanol-induced prolongation of shortening duration. In addition, short-term in vitro incubation of ethanol-induced cardiomyocyte mechanical defects were exacerbated by the ALDH inhibitor cyanamide. Ethanol treatment dampened phosphorylation of Akt and GSK-3β associated with up-regulated PP2A, which was accentuated by ALDH2 KO. ALDH2 KO aggravated ethanol-induced decrease in mitochondrial membrane potential. These results suggested that ALDH2 deficiency led to worsened ethanol-induced cardiomyocyte function, possibly due to upregulated expression of protein phosphatase, depressed Akt activation and subsequently impaired mitochondrial function. These findings depict a critical role of ALDH2 in the pathogenesis of alcoholic cardiomyopathy.
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影响因子：
4.7
作者：
Bijur, GN;Jope, RS
通讯作者：
Jope, RS
DOI：
10.1152/ajpheart.00780.2001
发表时间：
2002-04-01
影响因子：
4.8
作者：
Duan, JH;McFadden, GE;Ren, J
通讯作者：
Ren, J
影响因子：
7.7
作者：
Marmot, MG
通讯作者：
Marmot, MG
影响因子：
24
作者：
Ma, Heng;Li, Ji;Ren, Jun
通讯作者：
Ren, Jun
DOI：
10.1097/00001648-199009000-00003
发表时间：
1990-09-01
期刊：
Epidemiology (Cambridge, Mass.)
影响因子：
--
作者：
Boffetta, P;Garfinkel, L
通讯作者：
Garfinkel, L