(Circulation. 1997;95:1269-1277.)
© 1997 American Heart Association, Inc.
Articles |
cGMP-Elevating Agents Suppress Proliferation of Vascular Smooth Muscle Cells by Inhibiting the Activation of Epidermal Growth Factor Signaling Pathway
the Laboratory of Cardiovascular Science, Department of Pharmacology (S.M.Y., L.M.H., C.C.L.), Chang Gung College of Medicine and Technology, Kwei-San, Tao-Yuan, Taiwan, Republic of China.
Correspondence to Prof Sheu-Meei Yu, Laboratory of Cardiovascular Science, Department of Pharmacology, Chang Gung College of Medicine and Technology, 259 Wen-Hwa 1 Road, Kwei-San, Tao-Yuan, Taiwan, Republic of China.
Background Abnormal proliferation of vascular smooth muscle cells (VSMC) is a key event in the pathogenesis of atherosclerosis and many vascular diseases. It is known that nitric oxide released from the endothelium participates in the regulation of VSMC proliferation via a cyclic 3',5'-guanosine monophosphate (cGMP)-mediated mechanism. In a series of experiments, sodium nitroprusside (SNP) and A02131-1 were evaluated for their antiproliferative effect and the mechanism of their cGMP-elevating action.
Methods and Results The effect of SNP and A02131-1 on epidermal growth factor (EGF)-stimulated proliferation of rat aortic smooth muscle cells (VSMC) was examined. Cell proliferation was measured in terms of [3H]thymidine incorporation, flow cytometry, and the cell number. Further, their effect on the EGF-activated signal transduction pathway was assessed by measuring mitogen-activated protein kinases (MAPK), MAPK kinase (MEK), Raf-1 activity, and the formation of active form of Ras. SNP and A02131-1 inhibited EGF-induced DNA synthesis and subsequent proliferation of VSMC. These two increased cGMP but only a little cAMP in VSMC. A similar antiproliferative effect was observed with 8-bromo-cGMP. The antiproliferative effect of the two was reversed by KT5823 but not by dideoxyadenosine nor Rp-cAMPS. SNP and A02131-1 blocked the EGF-inducible cell cycle progression at the G1/S phase. Further experiments indicated that the two cGMP-elevating agents primarily blocked the activation of Raf-1 by EGF-activated Ras.
Conclusions These results demonstrate that cGMP-elevating agents inhibit [3H]thymidine incorporation and thus the growth of VSMC, and this inhibition appears to attenuate EGF-activated signal transduction pathway by preventing Ras-dependent activation of Raf-1.
Key Words: atherosclerosis • drugs • signal transduction • muscle, smooth • protein kinase
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