Expression of Cyclin-Dependent Kinase Inhibitors in Vascular Disease

From the Departments of Internal Medicine (F.C.T., Z.-Y.Y., E.D., G.J.N., E.G.N.), Physiology (E.G.N.), Biochemistry (G.J.N.), and Pathology (D.G.) and the Howard Hughes Medical Institute (Z.-Y.Y., G.J.N.), University of Michigan, Ann Arbor.

Correspondence to Elizabeth G. Nabel, University of Michigan, 7220 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail enabel{at}umich.edu

Abstract

Abstract—Arterial lesions in cardiovascular diseases are characterized by proliferation and migration of smooth muscle cells as well as deposition of connective tissue matrix. Factors that stimulate vascular smooth muscle cell (VSMC) proliferation are well described; however, the role of proteins that limit intimal hyperplasia is not well understood. To examine the function of Kip/Cip and INK cyclin-dependent kinase inhibitors (CKIs) in vascular diseases, the expression of p27^Kip1 and p16^INK was examined in VSMCs in vitro and in porcine arteries and human atherosclerosis in vivo. Western blot and fluorescence activated cell-sorting analysis demonstrated that levels of p27^Kip1, but not p16^INK, increased during serum deprivation of primary VSMC cultures and caused G₁ arrest. p27^Kip1 inhibited Cdk2 activity, suggesting that Kip CKIs promote G₁ arrest in VSMCs by binding cyclin E/Cdk2. In porcine arteries, p27^Kip1, but not p16^INK, was constitutively expressed at low levels. Immediately after balloon injury, cell proliferation increased as p27^Kip1 levels declined. Three weeks after injury, p27^Kip1 was strongly expressed in intimal VSMCs when VSMC proliferation was <2%, suggesting that p27^Kip1 functions as an inhibitor of cell proliferation in injured arteries. In contrast, p16^INK expression was detected only transiently early after injury. CKI expression was examined in 35 human coronary arteries, ranging from normal to advanced atherosclerosis. p27^Kip1 expression was abundant in nonproliferating VSMCs and macrophages within normal (7 of 8) and atherosclerotic (25 of 27) arteries. p21^Cip1 levels were undetectable in normal arteries but were elevated in atherosclerotic (19 of 27) arteries. p16^INK could not be detected in normal or atherosclerotic arteries (0 of 35). Thus, the Kip/Cip and INK CKIs have different temporal patterns of expression in VSMCs in vitro and in injured arteries and atherosclerotic lesions in vivo. In contrast to p16^INK, p27^Kip1 likely contributes to the remodeling process in vascular diseases by the arrest of VSMCs in the G₁ phase of the cell cycle.

Key Words: cyclin-dependent kinase • cell cycle • vascular smooth muscle cell

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