DOWN-REGULATION OF CYCLIN-DEPENDENT KINASE-2 ACTIVITY AND CYCLIN A PROMOTER ACTIVITY IN VASCULAR SMOOTH-MUSCLE CELLS BY P27(KIP1), INHIBITOR OF NEOINTIMA FORMATION IN THE RAT CAROTID-ARTERY

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contrib utes to intimal hyperplasia during atherosclerosis and restenosis, but the endogenous cell cycle regulatory factors underlying VSMC growth i n response to arterial injury are not well understood, In the present study, we report that downregulation of cyclin-dependent kinase 2 (cdk 2) activity in serum-deprived VSMCs was associated with the formation of complexes between cdk2 and its inhibitory protein p27(KIP1) (p27), Ectopic overexpression of p27 in serum-stimulated VSMCs resulted in th e inhibition of cdk2 activity and repression of cyclin A promoter acti vity, Collectively, these findings indicate that p27 may contribute to VSMC growth arrest in vitro, Using the rat carotid model of balloon a ngioplasty, a marked upregulation of p27 was observed in injured arter ies, High levels of p27 expression in the media and neointima correlat ed with downregulation of cdk2 activity at 2 wk after angioplasty, and adenovirus-mediated overexpression of p27 in balloon-injured arteries attenuated neointimal lesion formation, Thus, the inhibition of cdk2 function and repression of cyclin A gene transcription through the ind uction of the endogenous p27 protein provides a mechanism for the inhi bition of VSMC growth at late time points after angioplasty.