Alterations in insulin-like growth factor-I signaling in cardiomyocytes from chronic alcohol-exposed rats.
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)-alpha and that PKC-alpha 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-alpha activation by IGF-I, represented as a reduction in PKC-alpha translocation to the membrane. In reverse transcription-polymerase chain reaction experiments, both the alcoholic and control animals expressed the IGF-I receptor (IGF-1R, alpha 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 Mn2+ influx through activated nitrendipine-sensitive cardiac Ca2+ 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 Ca2+ 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 14C-L-phenylalanine incorporation over time, and this effect was blocked by preincubation with Gö6976, a specific inhibitor of PKC-alpha. 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-alpha 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-alpha.