REGULATION OF CARDIOMYOCYTE APOPTOTIC SIGNALING BY INSULIN-LIKE-GROWTH-FACTOR-I

Apoptosis is regulated by specific intracellular signaling pathways, T he development of cardiomyopathy involves the apoptosis of cardiomyocy tes; however, the details of their apoptotic signaling are not yet kno wn. Insulin-like growth factor I (IGF I) is an important survival grow th factor for myocardium and other tissues, but the effects of IGF I o n apoptotic signaling remain largely unknown. To study apoptotic signa ling pathways in cardiomyocytes and to understand IGF I actions on the apoptotic signaling of cardiac muscle cells, we have defined the effe cts of IGF I on Bcl-2, Bar, caspase 3, DNA fragmentation, and cell sur vival in primary cardiomyocytes. Compared with Bar levels, the levels of Bcl-2 were found to be quite low in these cells. Serum withdrawal a nd doxorubicin reduced cell viability, increased fragmentation of DNA, increased cellular contents of Bar, and activated caspase 3. IGF I en hanced cell viability, suppressed DNA fragmentation, attenuated Bar in duction, and suppressed caspase 3 activation. The levels of Bcl-2-asso ciated Bar were increased after serum withdrawal and incubation with d oxorubicin and were reduced by IGF I. Thus, cardiomyocyte apoptosis in duced by serum withdrawal and doxorubicin likely results, in part, fro m the induction of Bar and activation of caspase 3, but IGF I may inhi bit cardiomyocyte apoptosis by attenuating Bar induction and caspase 3 activation. These findings provide new insight into the mechanisms of cardiomyocytes apoptosis and may help elucidate how IGF I modulates a poptotic signaling in cardiac muscle.