ANGIOTENSIN-II INDUCES MONOCYTE CHEMOATTRACTANT PROTEIN-1 GENE-EXPRESSION IN RAT VASCULAR SMOOTH-MUSCLE CELLS

Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattra ctant protein-1 (MCP-I), Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-I gene expression in rat aortic smooth muscle cells, Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT(1) receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H2O2. with diphenylene iodonium or apoc ynin decreased Ang II-induced MCP-1 mRNA accumulation. Induction of MC P-1 gene expression by Ang Il was inhibited by catalase, suggesting a second messenger role for H2O2. The tyrosine kinase inhibitor genistei n and the mitogen-activated protein kinase kinase inhibitor PD098059 i nhibited Ang II-induced MCP-1 gene expression, consistent with a mitog en-activated protein kinase-dependent signaling mechanism, Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expressi on in vascular smooth muscle cells.