Duan Jinhong, McFadden Grant E, Borgerding Anthony J, Norby Faye L, Ren Bonnie H, Ye Gang, Epstein Paul N, Ren Jun
Department of Pharmacology, Physiology, and Therapeutics, Grand Forks, North Dakota 58203, USA.
Am J Physiol Heart Circ Physiol. 2002 Apr;282(4):H1216-22. doi: 10.1152/ajpheart.00780.2001.
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 Ca(2+) 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 Ca(2+) in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca(2+) 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.
酒精性心肌病的特征是心室功能受损，但其毒性机制尚不清楚。本研究检测了将乙醇氧化为乙醛（ACA）的乙醇脱氢酶（ADH）在心脏中过表达对乙醇诱导的心脏收缩缺陷的影响。评估了ADH转基因小鼠和野生型（FVB）小鼠心室肌细胞的力学和细胞内Ca(2+)特性。通过气相色谱法评估ACA的产生。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。急性暴露于乙醇会使FVB组的细胞缩短和细胞内Ca(2+)降低，最大抑制率分别为23.3%和23.4%。令人惊讶的是，ADH组中乙醇诱导的细胞缩短和细胞内Ca(2+)的降低显著增强，最大抑制率分别为43.7%和40.6%。用ADH抑制剂4-甲基吡唑（4-MP）或醛脱氢酶抑制剂氰胺预处理分别预防或增强了ADH组而非FVB组中乙醇诱导的抑制作用。ADH转基因还证实了乙醇诱导的缩短/再延长最大速度的抑制，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消除。这些数据表明，由于ADH表达增强导致的心脏ACA暴露增加可能在酒精性心肌病的发展中起重要作用。
