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GW23-e0847
DEFICIENCY OF INSULIN-LIKE GROWTH FACTOR 1 REDUCES VULNERABILITY TO CHRONIC ALCOHOL INTAKE-INDUCED CARDIOMYOCYTE MECHANICAL DYSFUNCTION: ROLE OF AMPK
  1. Wei Ge1,
  2. Qun Li2,
  3. Subat Turdi2,
  4. Xiao-Ming Wang1,
  5. Jun Ren2,
  6. Wei Ge1
  1. 1Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China
  2. 2Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA

    Abstract

    Objectives Circulating insulin-like growth factor I (IGF-1) levels are closely associated with cardiac performance although the role of IGF-1 in alcoholic cardiac dysfunction is unknown. This study was designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on chronic alcohol-induced cardiomyocyte contractile and intracellular Ca2+ dysfunction.

    Methods Adult male C57 and LID mice were placed on a 4% alcohol diet for 15 weeks. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dl/dt), time-to-relengthening (TR90), change in fura-fluorescence intensity (ΔFFI) and intracellular Ca2+ decay. Levels of apoptotic regulators caspase-3, Bcl-2 and c-Jun NH2-terminal kinase (JNK), the ethanol metabolising enzyme mitochondrial aldehyde dehydrogenase (ALDH2), as well as the cellular fuel gauge AMP-activated protein kinase (AMPK) were evaluated.

    Results Chronic alcohol intake enlarged myocyte cross-sectional area, reduced PS,±dL/dt and ΔFFI as well as prolonged TR90 and intracellular Ca2+ decay, the effect of which was greatly attenuated by IGF-1 deficiency. The beneficial effect of LID against alcoholic cardiac mechanical defect was ablated by IGF-1 replenishment. Alcohol intake increased caspase-3 activity/expression although it downregulated Bcl-2, ALDH2 and pAMPK without affecting JNK and AMPK. IGF-1 deficiency attenuated alcoholism-induced responses in all these proteins with the exception of Bcl-2. In addition, the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside abrogated short-term ethanol incubation-elicited cardiac mechanical dysfunction.

    Conclusions Taken together, these data suggested that IGF-1 deficiency may reduce the sensitivity to ethanol-induced myocardial mechanical dysfunction. Our data further depicted a likely role of Caspase-3, ALDH2 and AMPK activation in IGF-1 deficiency induced ‘desensitisation’ of alcoholic cardiomyopathy.

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