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Alterations in Insulin‐Like Growth Factor‐I Signaling in Cardiomyocytes From Chronic Alcohol‐Exposed Rats
Author(s) -
Pecherskaya Anna,
Rubin Emanuel,
Solem Michele
Publication year - 2002
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2002.tb02633.x
Subject(s) - autophosphorylation , medicine , endocrinology , protein kinase c , insulin like growth factor , growth factor , signal transduction , tyrosine kinase , myocyte , biology , receptor , protein kinase a , kinase , microbiology and biotechnology
Background Insulin‐like growth factor‐I (IGF‐I) is a required cytokine for the development and maintenance of the cardiovascular system, and it may play a role in certain pathophysiological conditions. Methods Adult male rats were fed a liquid diet that contained 36% alcohol for 4 to 8 months, and their littermates served as isocaloric pair‐fed controls, so we could examine IGF‐I signaling in rat cardiomyocyte preparations. Results Recently, our laboratory reported that IGF‐I activates protein kinase‐C (PKC)‐α and that PKC‐α activity is required for IGF‐I‐dependent activation of Erk1/Erk2 and IGF‐I‐dependent protein synthesis. But in chronic alcohol‐exposed rats, there is loss of PKC‐α activation by IGF‐I, represented as a reduction in PKC‐α translocation to the membrane. In reverse transcription‐polymerase chain reaction experiments, both the alcoholic and control animals expressed the IGF‐I receptor (IGF‐1R, α subunit) and IGF‐I mRNAs in approximately equal amounts. However, in the alcoholic cardiomyocyte protein preparations, there was a higher basal level of IGF‐1R autophosphorylation of its internal tyrosine kinase domain, and IGF‐I‐activated autophosphorylation was reduced in the alcoholic protein preparations. Previously, we have demonstrated that acute IGF‐I exposure enhances the rate of Mn 2+ influx through activated nitrendipine‐sensitive cardiac Ca 2+ channels, and that this enhancement of channel activity is PKC‐dependent. Here, we report that in alcohol‐exposed myocytes, IGF‐I‐induced augmentation of the cardiac Ca 2+ channel activity was absent. IGF‐I increased the rate of protein synthesis in the control animals by 56% as determined in protein synthesis experiments that measured the rate of 14 C‐L‐phenylalanine incorporation over time, and this effect was blocked by preincubation with Gö6976, a specific inhibitor of PKC‐α. However, in the alcohol‐exposed cardiomyocytes, IGF‐I did not increase the rate of protein synthesis. Conclusion These results suggest that IGF‐I‐dependent PKC‐α activation and IGF‐I‐dependent protein synthesis are altered in the hearts of chronic alcohol‐exposed rats. This may be the result of the IGF‐1R being in a chronically activated state, and it may alter the normal function of PKC‐α.