Differential regulation of Na+/H+ exchange and DNA synthesis in vascular smooth muscle cells

Na+/H+ exchange has been proposed to be involved in the regulation of cell growth. However, little is known about the regulatory pathway and relations hip between Na+/H+ exchange and DNA synthesis. In vascular smooth muscle ce lls, platelet-derived growth factor (a tyrosine kinase-coupled receptor ago nist) and thrombin (a G protein-coupled receptor agonist) stimulate both ac tivation of Na+/H+ exchange and DNA synthesis. In this study, we compared t he effect of platelet-derived growth factor (PDGF) and thrombin on the sign al transduction pathway leading to the activation of these responses in A10 cells, clonal rat thoracic aortic smooth muscle cells. To investigate the role of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3- kinase as potential mediators, we examined the effect of phar-macological k inase inhibitors on these responses. The Na+/H+ exchange activity induced b y thrombin was inhibited by a specific inhibitor of MAPK kinase, 2'-amino-3 '-methoxyflavone (PD98059), but was not affected by a specific phosphatidyl inositol-3-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4 H-1-benzopyran-4- one (LY294002). Thrombin-induced DNA synthesis was inhibited by LY294002, b ut not by PD98059. In contrast, the Na+/H+ exchange activity induced by PDG F was inhibited by neither LY294002 nor PD98059, but PDGF-induced DNA synth esis was inhibited, by both LY294002 and PD98059. These data suggest that, in A10 cells, Na+/H+ exchange activation and DNA synthesis are differently regulated by the two extracellular stimuli. (C) 1999 Elsevier Science B.V. All rights reserved.