Abstract
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)α in THP-1 cells, resulting in the up-regulation of α4 and β2 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.
Footnotes
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.127944.
-
ABBREVIATIONS: ACE, angiotensin I-converting enzyme; Ang, angiotensin; ACEI, angiotensin I-converting enzyme inhibitor; MCP, monocyte chemoattractant protein; PMA, phorbol 12-myristate 13-acetate; TPEN, N, N, N′, N′-tetrakis-(2-pyridylmethyl) ethylenediamine; PKC, protein kinase C; FCS, fetal calf serum; HUVEC, human umbilical vein endothelial cell; PBS, phosphate-buffered saline; IB, immunoblotting.
-
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received July 2, 2007.
- Accepted September 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|