Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Zhang, Rong-Huai¹  Gao, Jian-Yuan¹  Guo, Hai-Tao²  Scott, Glenda I.³  Eason, Anna R.³  Wang, Xiao-Ming¹  Ren, Jun^1,3 

[1] Fourth Mil Med Univ, Dept Geriatr, Xijing Hosp, Xian 710032, Shaanxi, Peoples R China

[2] Fourth Mil Med Univ, Dept Physiol, Xijing Hosp, Xian 710032, Shaanxi, Peoples R China

[3] Univ Wyoming, Coll Hlth Sci, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA

关键词: CYP2E1;    Cardiac function;    Apoptosis;    JNK;    ASK-1;    Stress signaling;   

DOI  :  10.1016/j.bbadis.2012.08.014

来源: Elsevier

【 摘 要 】

Alcohol intake is associated with myocardial contractile dysfunction and apoptosis although the precise mechanism is unclear. This study was designed to examine the effect of the cytochrome P450 enzyme CYP2E1 inhibition on ethanol-induced cardiac dysfunction. Adult male mice were fed a 4% ethanol liquid or pair-fed control diet for 6 weeks. Following 2 weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100 mg/kg/d, i.p.) for the remaining feeding duration. Cardiac function was assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate CYP2E1, heme oxygenase-1 (HO-1), iNOS, the intracellular Ca2+ regulatory proteins sarco(endo)plasmic reticulum Ca2+-ATPase, Na+-Ca2+ exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH2-terminal kinase (INK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na+-Ca2+ exchanger, cardiac contractile and intracellular Ca2+ defects, cardiac fibrosis, overt O-2(-) production, and apoptosis accompanied with increased phosphorylation of JNK and ASK-1, the effects were significantly attenuated or ablated by diallyl sulfide. Inhibitors of JNK and ASK-I but not HO-1 inducer or iNOS inhibitor obliterated ethanol-induced cardiomyocyte contractile dysfunction, substantiating a role for JNK and ASK-1 signaling in ethanol-induced myocardial injury. Taken together, these findings suggest that ethanol metabolism through CYP2E1 may contribute to the pathogenesis of alcoholic cardiomyopathy including myocardial contractile dysfunction, oxidative stress and apoptosis, possibly through activation of JNK and ASK-1 signaling. (C) 2012 Elsevier B.V. All rights reserved.

【 授权许可】

Free