Abstract
Monocyte chemoattractant protein-1 (MCP-1) is a potent chemotactic agent for monocytes and other cells and is thought to be involved in atherosclerosis, 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 freshly 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 μg/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-(dimethylamino)-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-stimulated MCP-1 production in freshly isolated human monocytes.
Footnotes
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This work was supported in part by a grant from Bristol-Myers Squibb (to L.J.B.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.047795.
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ABBREVIATIONS: MCP-1, monocyte chemoattractant protein-1; LDL, low-density lipoprotein; Ang II, angiotensin II; AT1, angiotensin II type 1; PAF, platelet-activating factor; AT2, angiotensin II type 2; c-PAF, carbamyl-PAF; HBSS, Hanks' balanced salt solution; HIFCS, heat-inactivated fetal calf serum; BSA, bovine serum albumin; HSA, human serum albumin; DMSO, dimethyl sulfoxide; fMLP, N-formylmethionyl-leucyl-phenylalanine; TXA2, thromboxane A2; HUVEC, human umbilical vein endothelial cell; PD123319, S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid; WEB 2086, 3-[4-(2-chlorophenyl)-9-methyl-6H-thienol-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine-2-yl]-1-(4-morpholynil)-1-propionate; CV11974, 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxic acid.
- Received December 19, 2002.
- Accepted February 24, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Angiotensin II Type 1 Receptor Antagonists Inhibit Basal As Well As Low-Density Lipoprotein and Platelet-Activating Factor-Stimulated Human Monocyte Chemoattractant Protein-1
