ACUTE MYOCARDIAL-INFARCTION LEADS TO UP-REGULATION OF THE IGF-1 AUTOCRINE SYSTEM, DNA-REPLICATION, AND NUCLEAR MITOTIC DIVISION IN THE REMAINING VIABLE CARDIAC MYOCYTES

Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are req uired for cell proliferation in vitro, raising the possibility that an autocrine IGF-1-IGF-1R system may be present in vivo and become activ ated in the viable ventricular myocytes shortly after infarction. Ther efore, following the in vivo documentation of left ventricular failure in rats subjected to occlusion of the left coronary artery, the unaff ected myocytes of the left ventricle were enzymatically dissociated an d the expression of IGF-1R and IGF-1 mRNAs were measured at 12 h and a t 1, 2-3, and 7 days after surgery. The level of expression of IGF-1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days followi ng coronary ligation. In addition, an increased level of IGF-1R protei n on these cells was found. This phenomenon was coupled with the enhan ced expression of IGF-1 mRNA in the muscle cells at all intervals. Myo cardial infarction was also accompanied by an upregulation of prolifer ating cell nuclear antigen (PCNA) mRNA in myocytes and the detection o f PCNA protein in nearly 1% of the cells. Similarly, bromodeoxyuridine labeling demonstrated that a comparable number of myocytes was positi vely stained. Finally, mitotic images in myocytes were observed. Thus, the IGF-1R-IGF-1 autocrine system may modulate myocyte cellular hyper plasia in the failing heart. (C) 1994 Academic Press, Inc.