Alcohol and Alcoholism Advance Access originally published online on October 4, 2006
Alcohol and Alcoholism 2006 41(6):585-592; doi:10.1093/alcalc/agl080
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CARDIAC OVEREXPRESSION OF METALLOTHIONEIN RESCUES CHRONIC ALCOHOL INTAKE-INDUCED CARDIOMYOCYTE DYSFUNCTION: ROLE OF AKT, MAMMALIAN TARGET OF RAPAMYCIN AND RIBOSOMAL P70S6 KINASE
Division of Pharmaceutical Sciences, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA
* Author to whom correspondence should be addressed. Tel: +1 307 766 6131; Fax: +1 307 766 2953; E-mail: jren{at}uwyo.edu
(Received 19 June 2006; first review notified 13 July 2006; in revised form 18 August 2006; accepted 29 August 2006)
Aims: Reduced insulin sensitivity following alcohol intake plays a role in alcohol-induced organ damage although its precise mechanism is undefined. This study was designed to examine the effect of cardiac overexpression of the antioxidant metallothionein on alcohol-induced cardiac contractile dysfunction and post-receptor insulin signaling. Methods: FVB and metallothionein mice were fed a 4% alcohol diet for 16 weeks. Cardiomyocyte contractile function was evaluated including peak shortening (PS), time-to-PS (TPS), and time-to-relengthening (TR90). Post-insulin receptor signaling molecules Akt, mammalian target of rapamycin (mTOR), and ribosomal p70s6 kinase (p70s6k) were evaluated using western blot analysis. Akt1 kinase activity was assayed with a phosphotransferase kit. Results: Alcohol intake dampened whole body glucose tolerance, depressed PS, shortened TPS, and prolonged TR90, which were abrogated by metallothionein with the exception of glucose intolerance. Our results revealed reduced expression of total Akt, phosphorylated mTOR, and phosphorylated p70s6k-to-p70s6k ratio as well as Akt1 kinase activity in alcohol consuming FVB mice. Phosphorylated Akt, total mTOR, and phosphorylated p70s6k were unaffected by alcohol. Metallothionein ablated reduced Akt protein and kinase activity without affecting any other proteins or their phosphorylation. Conclusion: In summary, our data suggest that chronic alcohol intake interrupted cardiac contractile function and Akt/mTOR/p70s6k signaling. Akt but unlikely mTOR and p70s6k may contribute to metallothionein-elicited cardiac protective response.
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