Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes
Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes
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DOI：
10.1152/ajpheart.00780.2001
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发表时间：
2002-04-01
影响因子：
4.8
通讯作者：
Ren, J
中科院分区：
文献类型：
--
作者：
Duan, JH;McFadden, GE;Ren, J
酒精性心肌病的特点是心室功能受损，但其毒性机制尚不清楚。本研究检测了心脏过度表达乙醇脱氢酶（ADH）对乙醇诱导的心脏收缩性缺陷的影响。乙醇脱氢酶能将乙醇氧化为乙醛（ACA）。对ADH转基因和野生型（FVB）小鼠心室肌细胞的力学和细胞内Ca2+特性进行了评价。用气相色谱法测定ACA的产量。与FVB肌细胞相比，ADH肌细胞表现出相似的力学特性，但转化ACA的效率更高。急性暴露于乙醇抑制FVB组细胞缩短和细胞内Ca2+，最大抑制分别为23.3%和23.4%。引人注目的是，乙醇诱导的细胞缩短和细胞内Ca2+的抑制在ADH组显著增强，最大抑制分别为43.7%和40.6%。ADH抑制剂4-甲基吡唑（4-MP）或醛脱氢酶抑制剂氰酰胺预处理分别阻止或增强ADH组乙醇诱导的抑制作用，但对FVB组没有作用。ADH转基因也证实了乙醇诱导的最大缩短/再延长速度的抑制作用，并揭示了乙醇诱导的缩短/再延长持续时间的延长，这被4-MP所消除。这些数据表明，由于ADH表达增强导致的心脏ACA暴露升高可能在酒精性心肌病的发展中起重要作用。
Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular Ca2+ properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular Ca2+ in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca2+ was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy.