Persistent and Heterogenous Expression of the Cyclin-dependent Kinase Inhibitor, p27KIP1, in Rat Hearts During Developmen

We have previously shown that there were differential and dramatic decreases of cyclin and cyclin-dependent kinase (CDK) activities in cardiomyocytes during the neonatal period. The activity of CDKs control cell cycle progression, and this activity is regulated positively and negatively by association of CDKs with cyclins and cyclin-dependent kinase inhibitors (CKIs), respectively. While the INK family (p15INK4B/p16INK4A/p18INK4C/p19INK4D) of CKIs is not detectable in hearts, the KIP/CIP family (p21CIP1, p27KIP1and p57KIP2) of CKIs is detectable in most organs including the heart. Differential and dramatic changes of the KIP/CIP family (p21CIP1, p27KIP1and p57KIP2) of CKIs were detected in rat hearts during development. The mRNA and protein levels of p21CIP1and p57KIP2were readily detectable in hearts at gestational and early postnatal periods and decreased thereafter. The mRNA levels of p27KIP1in ventricles were high during the gestational period, and did not change until day 30 postnatal, then were decreased slightly in 90-day-old rats. The protein levels of p27KIP1increased significantly in the early postnatal period, then were expressed persistently, although levels decreased slightly in the adult period. However, protein levels of p27KIP1in atria did not change during development. Variable immuno-staining patterns of p27KIP1were observed at different periods of development and in various locations in myocardium. During the gestational period, approximately 35–50% of myocardial cells in the cardiac wall were p27KIP1immuno-positive and were distributed diffusely. These p27KIP1immunopositive cells increased predominantly in endocardial and mid-portion areas of ventricular myocardium at the early postnatal period. This heterogenous pattern of p27KIP1protein expression persisted to adult hearts though the percentage of p27KIP1immuno-positive cells decreased slightly. High magnification revealed that more than 50% of adult cardiomyocytes were p27KIP1immuno-positive and that p27KIP1was located solely in nuclei. These results indicate that p27KIP1may be an important inhibitor of CDK activities in cardiomyocytes during early postnatal development and may block the re-entrance of adult cardiomyocytes into the cell cycle after injury.