A novel role for the cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy

Citation
Rc. Braun-dullaeus et al., A novel role for the cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy, J CLIN INV, 104(6), 1999, pp. 815-823
Citations number
40
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
00219738 → ACNP
Volume
104
Issue
6
Year of publication
1999
Pages
815 - 823
Database
ISI
SICI code
0021-9738(199909)104:6<815:ANRFTC>2.0.ZU;2-#
Abstract
Angiotensin II (Ang II) has been shown to stimulate either hypertrophy or h yperplasia. We postulated that the differential response of vascular smooth muscle cells (VSMCs) to Ang II is mediated by the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1), which is abundant in quiescent cells and drops a fter serum stimulation. Ang II treatment (100 nM) of quiescent VSMCs led to upregulation of the cell-cycle regulatory proteins cyclin D1, Cdk2, prolif erating cell nuclear antigen, and Cdk1. p27(Kip1) levels, however, remained high, and the activation of the G1-phase Cdk2 was inhibited as the cells u nderwent hyper trophy. Overexpression of p27(Kip1) cDNA inhibited serum-sti mulated [H-3] thymidine incorporation compared with control-transfected cel ls. This cell-cycle inhibition was associated with cellular hypertrophy, as reflected by an increase in the [H-3]leucine/[H-3]thymidine incorporation ratio and by an increase in forward-angle light scatter during flow cytomet ry at 48 hours after transfection. The role of p27(Kip1) in modulating the hypertrophic response of VSMCs to Ang II was further tested by antisense ol igodeoxynucleotide (ODN) inhibition of p27(Kip1) expression. Ang II stimula ted an increase in [H-3] thymidine incorporation and the percentage of S-ph ase cells in antisense ODN-transfected cells but not in control ODN-transfe cted cells. We conclude that p27(Kip1) plays a role in mediating VSMC hyper trophy. Ang II stimulation of quiescent cells in which p27(Kip1) levels are high results in hypertrophy but promotes hyperplasia when levels of p27(Ki p1) are low, as in the presence of other growth factors.