title: Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.
abstract: 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 6weeks. Following 2weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100mg/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 Ca(2+) regulatory proteins sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)Ca(2+) exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH(2)-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na(+)Ca(2+) exchanger, cardiac contractile and intracellular Ca(2+) 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-1 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.
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Rong-Huai
authors.initials: RH
authors.lastname: Zhang
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Gao
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Guo
authors.forename: Glenda I
authors.initials: GI
authors.lastname: Scott
authors.forename: Anna R
authors.initials: AR
authors.lastname: Eason
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D015536:Down-Regulation; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1