A novel role for the cyclin-dependent kinase inhibitor p27(Kip1) in angiotensin II-stimulated vascular smooth muscle cell hypertrophy.
Angiotensin II (Ang II) has been shown to stimulate either hypertrophy or hyperplasia. 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 after serum stimulation. Ang II treatment (100 nM) of quiescent VSMCs led to upregulation of the cell-cycle regulatory proteins cyclin D1, Cdk2, proliferating cell nuclear antigen, and Cdk1. p27(Kip1) levels, however, remained high, and the activation of the G1-phase Cdk2 was inhibited as the cells underwent hypertrophy. Overexpression of p27(Kip1) cDNA inhibited serum-stimulated [(3)H]thymidine incorporation compared with control-transfected cells. This cell-cycle inhibition was associated with cellular hypertrophy, as reflected by an increase in the [(3)H]leucine/[(3)H]thymidine incorporation ratio and by an increase in forward-angle light scatter during flow cytometry 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 oligodeoxynucleotide (ODN) inhibition of p27(Kip1) expression. Ang II stimulated an increase in [(3)H]thymidine incorporation and the percentage of S-phase cells in antisense ODN-transfected cells but not in control ODN-transfected cells. We conclude that p27(Kip1) plays a role in mediating VSMC hypertrophy. Ang II stimulation of quiescent cells in which p27(Kip1) levels are high results in hypertrophy but promotes hyperplasia when levels of p27(Kip1) are low, as in the presence of other growth factors.
Braun-Dullaeus
R C
RC
Division of Cardiology, Giessen University, 35392 Giessen, Germany.
Mann
M J
MJ
Ziegler
A
A
von der Leyen
H E
HE
Dzau
V J
VJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006984:Hypertrophy; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27