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.