Angiotensin-converting enzyme inhibitor attenuates monocyte adhesion to vascular endothelium through modulation of intracellular zinc.
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)alpha in THP-1 cells, resulting in the up-regulation of alpha4 and beta2 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.
Kojima
Chiari
C
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45 Yushima Bldg. D-9, Bunkyo-ku, Tokyo 113-8519, Japan.
Kawakami
Akio
A
Takei
Takashi
T
Nitta
Kosaku
K
Yoshida
Masayuki
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D015151:Immunoblotting; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D007703:Peptidyl-Dipeptidase A; C078006:imidaprilat