© 1996 American Heart Association, Inc.
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Ca2+-Dependent Mitogen-Activated Protein Kinase Activation in Spontaneously Hypertensive Rat Vascular Smooth Muscle Defines a Hypertensive Signal Transduction Phenotype
From the Departments of Physiology (P.A.L., J.M.B.) and Medicine (K.L.B.), Loyola University Medical School, Maywood, Ill, and the Department of Medicine (L.S.W., M.A.C., B.C.B.), Division of Cardiology, University of Washington, Seattle.
Correspondence to Dr Pamela A. Lucchesi, Department of Physiology and the Cardiovascular Research Institute, Loyola University Medical School, 2160 S First Ave, Maywood, IL 60153. E-mail plucche@wpo.it.luc.edu.
Abstract The mechanisms responsible for altered vascular smooth muscle cell (VSMC) function in hypertension remain unknown. In the spontaneously hypertensive rat (SHR) model of genetic hypertension, there are multiple abnormalities in VSMC function, including increased growth, Na+-H+ exchange, and increased signal transduction by protein kinase C. The family of kinases termed mitogen-activated protein (MAP) kinases has recently been shown to be essential mediators of growth factor signal transduction. In the present study, alterations in MAP kinase function in the hypertensive phenotype were investigated using early-passage SHR and Wistar-Kyoto (WKY) VSMCs stimulated with angiotensin II (Ang II, 100 nmol/L) or platelet-derived growth factor-BB (PDGF-BB, 10 ng/mL). MAP kinase activity was measured by in-gel kinase assays and Western blot analysis. Two differences between SHR and WKY rats were observed for Ang II–mediated MAP kinase activation: (1) Inactivation after Ang II stimulation was more rapid in SHR than WKY VSMCs. (2) Activity in SHR VSMCs showed a greater dependence on Ca2+ mobilization, since chelation of intracellular Ca2+ with BAPTA inhibited maximal activity by 95% in SHR VSMCs but by only 50% in WKY VSMCs. In contrast to the results with Ang II, no differences in PDGF-stimulated MAP kinase activity were observed. These findings establish activation of MAP kinase by Ang II as a feature that distinguishes SHR VSMCs from WKY VSMCs and suggest that differences in regulation of MAP kinase signaling may alter cellular events that are increased in the SHR genetic model of hypertension.
Key Words: vascular smooth muscle • hypertension • kinase • phosphatase • signal transduction
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