Angiotensin II Type 1 Receptor Antagonists Inhibit Basal As Well As Low-Density Lipoprotein and Platelet-Activating Factor-Stimulasted Human Monocyte Chemoattractant Protein-1

摘要

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemotactic agent for monocytes and other cells and is thought to be involved in atherosclrerosis, recruiting monocytes to the subendothelial space or to the site of inflammation. Angiotensin II has been demonstrated, at least in animal models, to stimulate MCP-1 expression. We investigated the effect of the angiotensin II type 1 (AT1) receptor antagonists irbesartan and losartan on MCP-1 production by fleshly isolated human monocytes. Irbesartan and losartan inhibited basal MCP-1 production in a dose-dependent manner. Low-density lipoprotein (LDL) stimulated MCP-1 in a concentration-dependent manner, with 200 mug/ml LDL protein giving a 2-fold increase in MCP-1. Irbesartan and losartan dose dependently blocked LDL-stimulated MCP-1. An angiotensin II type 2 receptor antagonist, S-(+)-1-([4-(dimenthylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid (PD123319), had no significant effect on basal MCP-1 levels or LDL-stimulated MCP-1. After noting homology between the AT1 receptor and the platelet-activating factor (PAF) receptor, we showed that irbesartan inhibited both [~3H]PAF binding to human monocytes and carbamyl-PAF stimulation of MCP-1. However, irbesartan affinity for the PAF receptor was 700 times less than PAF, suggesting that there may be another mechanism for irbesartan inhibition of PAF-stimulated MCP-1. This is the first report showing that AT1 receptor antagonists inhibit basal as well as LDL- and PAF-receptor antagonists inhibit basal as well as LDL- and PAF-stimulated MCP-1 production in freshly isolated human monocytes.