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

Felix C. Tanner, Manfred Boehm, Levent M. Akyürek, Hong San, Zhi Yong Yang, Jun Tashiro, Gary J. Nabel, Elizabeth G. Nabel

Research output: Contribution to journalArticle

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 G1 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 G1 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% (P1 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.

Original languageEnglish (US)
Pages (from-to)2022-2025
Number of pages4
JournalCirculation
Volume101
Issue number17
StatePublished - May 2 2000
Externally publishedYes

Keywords

  • Cell cycle
  • Cell division
  • Cyclin-dependent kinases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Tanner, F. C., Boehm, M., Akyürek, L. M., San, H., Yang, Z. Y., Tashiro, J., Nabel, G. J., & Nabel, E. G. (2000). Differential effects of the cyclin-dependent kinase inhibitors p27(Kip1), p21(Cip1) and p16(Ink4) on vascular smooth muscle cell proliferation. Circulation, 101(17), 2022-2025.