Am. J. Respir. Cell Mol. Biol., Volume 25, Number 5, November, 2001 652-658

p27^Kip1 Is Important in Modulating Pulmonary Artery Smooth Muscle Cell Proliferation

Brian W. Fouty, Bryn Grimison, Karen A. Fagan, Timothy D. Le Cras, Julie W. Harral, Marloes Hoedt-Miller, Robert A. Sclafani, and David M. Rodman

Center for Genetic Lung Disease and Division of Pulmonary Sciences and Critical Care Medicine, Department of Biochemistry and Molecular Genetics, Department of Pediatrics, and Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado

Vascular remodeling due to pulmonary arterial smooth muscle cell (PASMC) proliferation is central to the development of pulmonary hypertension. Cell proliferation requires the coordinated interaction of cyclins and cyclin-dependent kinases (cdk) to drive cells through the cell cycle. Cdk inhibitors can bind cyclin-cdk complexes and cause G₁ arrest. To determine the importance of the cdk inhibitor p27^Kip1 in PASMC proliferation we studied [³H]thymidine incorporation, changes in cell cycle, cell proliferation, and protein expression of p27^Kip1 following serum stimulation in early passage rat PASMC. p27^Kip1 expression decreased to 40% of baseline after serum stimulation, which was associated with an increase in both [³H]thymidine incorporation and the percent of cells in S phase. p27^Kip1 binding to cyclin E decreased at 24 h, and this correlated with an increase in phosphorylation of retinoblastoma both in vivo and in vitro. Overexpression of p27^Kip1 decreased [³H]thymidine incorporation and reduced cell counts at 5 d compared with controls. PASMC obtained from p27^Kip1/ mice showed a 2-fold increase in [³H]thymidine incorporation (at 24 h) and cell proliferation compared with p27^Kip1+/+ PASMC when cultured in 10% fetal bovine serum (FBS). These results suggest an important role for p27^Kip1 in regulating PASMC mitogenesis and proliferation.

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