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Apolipoprotein C-I is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E-knockout mice

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Author: Westerterp, M. · Berbée, J.F.P. · Pires, N.M.M. · Mierlo, G.J.D. van · Kleemann, R. · Romijn, J.A. · Havekes, L.M. · Rensen, P.C.N.
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Circulation, 19, 116, 2173-2181
Identifier: 240260
doi: doi:10.1161/CIRCULATIONAHA.107.693382
Keywords: Biomedical Research · Apolipoproteins · Atherosclerosis · Hypercholesterolemia · Inflammation · Leukocytes · Lipoproteins · apolipoprotein C1 · apolipoprotein E · bacterium lipopolysaccharide · endothelial leukocyte adhesion molecule 1 · fibrinogen · tumor necrosis factor alpha · animal cell · animal experiment · animal model · animal tissue · aorta atherosclerosis · aorta root · article · atherogenesis · atherosclerosis · bacterial infection · controlled study · female · fibrinogen blood level · inflammation · knockout mouse · macrophage · mouse · nonhuman · priority journal · protein blood level · protein expression · Animals · Apolipoproteins C · Atherosclerosis · Biological Markers · Cells, Cultured · Cholesterol, HDL · E-Selectin · Female · Fibrinogen · Hypercholesterolemia · Lipopolysaccharides · Macrophages, Peritoneal · Male · Mice · Mice, Inbred C57BL · Mice, Mutant Strains · Monocytes · T-Lymphocytes · Tumor Necrosis Factor-alpha · Vasculitis

Abstract

BACKGROUND - Lipopolysaccharide (LPS), which is released from Gram-negative bacteria on multiplication or lysis, aggravates atherosclerosis in humans and rodents by inducing inflammation via toll-like receptors. Because apolipoprotein C-I (apoCI) enhances the LPS-induced inflammatory response in macrophages in vitro and in mice, we investigated the effect of endogenous apoCI expression on LPS-induced atherosclerosis in mice. METHODS AND RESULTS - Twelve-week-old apoeapoc1 and apoeapoc1 mice received weekly intraperitoneal injections of LPS (50 μg) or vehicle for a period of 10 weeks, and atherosclerosis development was assessed in the aortic root. LPS administration did not affect atherosclerotic lesion area in apoeapoc1 mice but increased it in apoeapoc1 mice. In fact, apoCI expression increased the LPS-induced atherosclerotic lesion area by 60% (P<0.05), concomitant with an increase in LPS-induced plasma levels of fibrinogen and E-selectin. This indicated that apoCI increased the LPS-induced inflammatory state, both systemically (ie, fibrinogen) and at the level of the vessel wall (ie, E-selectin). In addition, both macrophage-derived apoCI and HDL-associated apoCI increased the LPS-induced tumor necrosis factor-α response by macrophages in vitro. CONCLUSIONS - We conclude that apoCI is crucially involved in LPS-induced atherosclerosis in apoe mice, which mainly relates to an increased inflammatory response toward LPS. We anticipate that apoCI plasma levels contribute to accelerated atherosclerosis development in individuals who have chronic infection. © 2007 American Heart Association, Inc.