Differential effects of the cyclin-dependent kinase inhibitors p27(Kip1), p21(Cip1), and p16(Ink4) on vascular smooth muscle cell proliferation

Background-The cyclin-dependent kinase inhibitors (CKIs) have different pat terns of expression in vascular diseases. The Kip/Cip CKIs, p27(Kip1) and p 21(Cip1), are upregulated during arterial repair and negatively regulate th e growth of vascular smooth muscle cells (VSMCs). In contrast, the Ink CKI, p16(Ink4), is not expressed in vascular lesions. We hypothesized that a va riation in the inactivation of cdk3 and cdk4 during the G(1) phase of the c ell cycle by p27(Kip1), p21(Cip1) and p16(Ink4) leads to different effects on VSMC growth in vitro and in vivo. Methods and Results-The expression of p27(Kip1) and p21(Cip1), serum-stimul ated VSMCs inactivated cdk2 and cdk4, leading to G(1) growth arrest, p16(In k4) inhibited cdk4, but not cdk2, kinase activity, producing partial inhibi tion of VSMC growth in vitro. In an in vivo model of vascular injury, overe xpression of p27(Kip1) reduced intimal VSMC proliferation by 52% (P<0.01) a nd the intima/media area ratio by 51% (P<0.005) after vascular injury and g ene transfer to pig arteries, when compared with control arteries. p16(Ink4 ) was a weak inhibitor of intimal VSMC proliferation in injured arteries (P =NS), and it did not significantly reduce intima/media area ratios (P=NS), which is consistent with its minor effects on VSMC growth in vitro. Conclusions-p27(Kip1) and p21(Cip1) are potent inhibitors of VSMC growth co mpared with p16(Ink4) because of their different molecular mechanisms of cy clin-dependent kinase inhibition in the G(1) phase of the cell cycle. These findings have important implications for our understanding of the pathophy siology of vascular proliferative diseases and for the development of molec ular therapies.