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CARDIOVASCULAR

Angiotensin-Converting Enzyme Inhibitor Attenuates Monocyte Adhesion to Vascular Endothelium through Modulation of Intracellular Zinc

Life Science and Bioethics Research Center (C.K., A.K., M.Y.) and Geriatrics and Vascular Medicine (A.K.), Tokyo Medical and Dental University, Tokyo, Japan; and Department of Medicine IV, Tokyo Women's Medical University, Tokyo, Japan (C.K., T.T., K.N.)

To elucidate an anti-inflammatory role of angiotensin-converting enzyme inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in monocyte adhesion to endothelial cells and underlying molecular mechanisms. Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar effects were obtained with experiments using human peripheral monocytes (P < 0.05). MCP-1 activated protein kinase C (PKC) in THP-1 cells, resulting in the up-regulation of 4 and 2 integrin. Imidaprilat attenuated MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as well as PKC inhibitor inhibited these processes, suggesting the role for labile zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel anti-inflammatory mechanism of ACEIs in atherogenesis.

Address correspondence to: Dr. Masayuki Yoshida, Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45 Yushima Bldg. D-9, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: masavasc{at}tmd.ac.jp