INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR AND ITS LIGAND REGULATE THE REENTRY OF ADULT VENTRICULAR MYOCYTES INTO THE CELL-CYCLE

To determine whether insulin-like growth factor-1 (IGF-1) stimulation in vitro of ventricular myocytes isolated from infarcted hearts is cha racterized by the reentry of cells into the cell cycle, the expression and kinase activity of cyclins E, A, and E and DNA synthesis were eva luated 5 days after coronary artery occlusion and 24 and 48 h followin g the addition of IGF-1. Myocytes surviving an acute myocardial infarc tion were employed because of their increase in surface insulin-like g rowth factor-1 receptors (IGF-1R). Western blot analysis documented th at IGF-1 resulted in an upregulation of cyclins D-1, E, A, and B in vi able postinfarcted myocytes. Cyclin E-and A-associated histone H-1, ki nase activity and cyclin D-1-associated retinoblastoma protein-associa ted kinase activity also increased, but cyclin B kinase activity was n ot enhanced by IGF-1. These changes in cyclins and kinase activities w ere characterized by a significant increase in the number of cells lab eled by bromodeoxyuridine, from approximately 630/10(6) to nearly 9,00 0/10(6) myocytes, This latter value was reduced by more than 50% by an tisense oligodeoxynucleotide to IGF-1R mRNA. However, IGF-1 stimulatio n did not induce nuclear mitotic division and cytokinesis. In conclusi on, the growth-promoting effect of IGF-1 on adult myocytes is regulate d by the density of IGF-1R, which conditions the activation of the rep licatory machinery of the cells. The failure of IGF-1 to enhance cycli n B kinase activity may be responsible for a block in the cell cycle a nd the inability of myocytes to progress through the M phase and subse quently divide. (C) 1997 Academic Press.