© 1999 American Heart Association, Inc.
Molecular Medicine |
Distinct Role of cAMP and cGMP in the Cell Cycle Control of Vascular Smooth Muscle Cells
cGMP Delays Cell Cycle Transition Through Suppression of Cyclin D1 and Cyclin-Dependent Kinase 4 Activation
From the Second Department of Internal Medicine (S.F., H.K., M.H., K.Y., S.T., H.M., Y.N.), Osaka City University Medical School, Osaka, Japan. Dr Hosoi’s current address is Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan.
Correspondence to Hidenori Koyama, MD, PhD, Second Department of Internal medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail hidekoyama{at}med.osaka-cu.ac.jp
Abstract—cAMP and cGMP are known to suppress vascular smooth muscle cell (SMC) proliferation. In this study, our aim was to delineate the molecular mechanism underlying cAMP and cGMP suppression of cell cycle transition in human SMCs. cAMP inhibits both platelet-derived growth factor–stimulated cyclin-dependent kinase (cdk) 2 and cdk4 activation through upregulation of the cdk2 inhibitor p27Kip1 and downregulation of cyclin D1 expression, which leads to a complete arrest of the cells in phase G1. In contrast, cGMP inhibits cyclin D1 expression, inhibits cdk4 activation, and delays platelet-derived growth factor–mediated cdk2 activation, resulting in a delay in G1/S transition. A transient increase in p27Kip1 in cdk2 immunoprecipitates, without changes in total cellular p27Kip1 levels, correlates with the delay in cdk2 activation caused by cGMP. Thus, cAMP and cGMP differentially affect cell cycle through distinct regulation of cell cycle molecules in human SMCs.
Key Words: p27Kip1 • platelet-derived growth factor • kinase
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