Cell cycle profiles and expressions of p21(CIP1) and p27(KIP1) during myocyte development

The ability of the cardiac myocyte to divide ceases shortly after birth. Th us, following severe injury, e.g., during myocardial infarction, the mature heart is unable to regenerate new tissue to replace the dead or damaged ti ssue. The identification of the molecules controlling the cessation of myoc yte cell division may lead to therapeutic strategies which aim to re-popula te the damaged myocardial area. Hence, we have determined the cell cycle pr ofile, expressions and activities of the cyclin-dependent kinase inhibitors (CDKIs), p21(CIP1) and p27(KIP1), during rat ventricular myocyte developme nt. Fluorescent activated cell sorting (FACS) analyses showed the percentag e of S phase myocytes to be decreased significantly throughout development, concomitant with a significant increase in the percentage of G(0)/G(1) and G(2)/M phase cells. The expression of p21(CIP1) and p27(KIP1) increased si gnificantly throughout cardiac development and complexed differentially wit h a number of cyclins and CDKs. Furthermore, an adult myocyte extract reduc ed neonatal myocyte CDK2 kinase activity significantly (>30%, p<0.05) where as immunodepletion of p21(CIP1) from adult lysates restored CDK2 kinase act ivity. Thus, p21(CIP1) and p27(KIP1) may be important for the withdrawal of cardiac myocytes from the cell cycle and for maintaining the G(0)/G(1) and G(2)/M phase blockades. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.