IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart

Bcl-2 family proteins play a crucial role in the cytoprotective action of i nsulin-like growth factor-I (IGF-I) by regulating cell death signaling at t he mitochondrial level. The present study examined the effect of IGF-I on t he expression of Bcl-2 family proteins in the rat heart mitochondria in rel ation to myocardial protection against ischemia-reperfusion injury. Systemi c IGF-I (1 mg) treatment in the rat increased Bcl-xL and attenuated Bax 12- 24 h later in the heart mitochondria fraction. Permeability transition and cytochrome c release occurred in a Ca2+ concentration-dependent manner in t he vehicle-treated mitochondria. This was significantly inhibited by the IG F-I-pretreatment. Moreover, ATP synthesis was significantly greater in the IGF-I-pretreated mitochondria. IGF-I pretreatment 24 h before 25 min of glo bal ischemia in the isolated rat heart model significantly improved recover y of isovolumic left ventricular function and inhibited creatine kinase rel ease during reperfusion. This was associated with a significantly less numb er of terminal transferase labeling-positive myocytes and nonmyocytes 2 h a fter reperfusion. These results suggest that IGF-1 differentially regulates Bcl-xL and Bax in heart mitochondria, which may be causally related to myo cardial protection against ischemia-reperfusion injury.