Differential Effects of the Cyclin-Dependent Kinase Inhibitors p27 Kip1 , p21 Cip1 , and p16 Ink4 on Vascular Smooth Muscle Cell Proliferation

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Abstract
Background —The cyclin-dependent kinase inhibitors (CKIs) have different patterns of expression in vascular diseases. The Kip/Cip CKIs, p27 Kip1 and p21 Cip1 , are upregulated during arterial repair and negatively regulate the growth of vascular smooth muscle cells (VSMCs). In contrast, the Ink CKI, p16 Ink4 , is not expressed in vascular lesions. We hypothesized that a variation in the inactivation of cdk2 and cdk4 during the G 1 phase of the cell 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 in serum-stimulated VSMCs inactivated cdk2 and cdk4, leading to G 1 growth arrest. p16 Ink4 inhibited cdk4, but not cdk2, kinase activity, producing partial inhibition of VSMC growth in vitro. In an in vivo model of vascular injury, overexpression of p27 Kip1 reduced intimal VSMC proliferation by 52% ( P P 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 compared with p16 Ink4 because of their different molecular mechanisms of cyclin-dependent kinase inhibition in the G 1 phase of the cell cycle. These findings have important implications for our understanding of the pathophysiology of vascular proliferative diseases and for the development of molecular therapies.