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(Circulation. 2007;116:2173-2181.)
© 2007 American Heart Association, Inc.

Vascular Medicine

Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E–Knockout Mice

Marit Westerterp, PhD^*; Jimmy F.P. Berbée, PhD^*; Nuno M.M. Pires, PhD; Geertje J.D. van Mierlo, PhD; Robert Kleemann, PhD; Johannes A. Romijn, MD, PhD; Louis M. Havekes, PhD; Patrick C.N. Rensen, PhD

From The Netherlands Organization for Applied Scientific Research–Quality of Life (M.W., J.F.P.B., N.M.M.P., R.K., L.M.H., P.C.N.R.), Department of Biomedical Research, Gaubius Laboratory, Leiden, the Netherlands; and Departments of General Internal Medicine, Endocrinology, and Metabolic Diseases (M.W., J.F.P.B., J.A.R., L.M.H., P.C.N.R.), Cardiology (N.M.M.P., L.M.H.), Rheumatology (G.J.D.v.M.), and Vascular Surgery (R.K.), Leiden University Medical Center, Leiden, the Netherlands.

Correspondence to Marit Westerterp, Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, C4-R, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail M.Westerterp{at}lumc.nl

Received January 30, 2007; accepted August 31, 2007.

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 apoe^–/–apoc1^–/– and apoe^–/–apoc1^+/+ 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 apoe^–/–apoc1^–/– mice but increased it in apoe^–/–apoc1^+/+ 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- 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.

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