(Circulation. 2000;101:2022.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Differential Effects of the Cyclin-Dependent Kinase Inhibitors p27Kip1, p21Cip1, and p16Ink4 on Vascular Smooth Muscle Cell Proliferation
From the Departments of Internal Medicine (F.C.T., M.B., L.M.A., H.S., Z.-Y.Y., J.T., G.J.N., E.G.N.) and Physiology (E.G.N.), University of Michigan, Ann Arbor; and the National Heart, Lung, and Blood Institute (M.B., L.M.A., H.S., E.G.N.) and the Vaccine Research Center (Z.-Y.Y., G.J.N.), National Institutes of Health, Bethesda, Md.
Correspondence to Elizabeth G. Nabel, NIH, NHLBI, Building 10/Room 8C103, Bethesda, MD 20892. E-mail enabel{at}nih.gov
Background—The cyclin-dependent kinase inhibitors (CKIs) have different patterns of expression in vascular diseases. The Kip/Cip CKIs, p27Kip1 and p21Cip1, are upregulated during arterial repair and negatively regulate the growth of vascular smooth muscle cells (VSMCs). In contrast, the Ink CKI, p16Ink4, is not expressed in vascular lesions. We hypothesized that a variation in the inactivation of cdk2 and cdk4 during the G1 phase of the cell cycle by p27Kip1, p21Cip1, and p16Ink4 leads to different effects on VSMC growth in vitro and in vivo.
Methods and Results—The expression of p27Kip1 and p21Cip1 in serum-stimulated VSMCs inactivated cdk2 and cdk4, leading to G1 growth arrest. p16Ink4 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 p27Kip1 reduced intimal VSMC proliferation by 52% (P<0.01) and the intima/media area ratio by 51% (P<0.005) after vascular injury and gene transfer to pig arteries, when compared with control arteries. p16Ink4 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—p27Kip1 and p21Cip1 are potent inhibitors of VSMC growth compared with p16Ink4 because of their different molecular mechanisms of cyclin-dependent kinase inhibition in the G1 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.
Key Words: cell cycle • cell division • cyclin-dependent kinases
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