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

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 apoe Ϫ/Ϫ apoc1 Ϫ/Ϫ and apoe Ϫ/Ϫ apoc1 ϩ/ϩ mice received weekly intraperitoneal injections of LPS (50 g) 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 Ϫ/Ϫ apoc1 Ϫ/Ϫ mice but increased it in apoe Ϫ/Ϫ apoc1 ϩ/ϩ mice. In fact, apoCI expression increased the LPS-induced atherosclerotic lesion area by 60% (PϽ0.05), 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 Ϫ/Ϫ 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.

Apolipoprotein CI enhances the biological response to LPS via the CD14/TLR4 pathway by LPS-binding elements in both its N- and C-terminal helix

“…By enhancing the biological response toward LPS and Gram-negative bacteria, apoCI improved the antibacterial attack, reduced bacterial outgrowth, and protected against intrapulmonal Klebsiella pneumoniae -induced fatal sepsis ( 19 ). Moreover, by enhancing the systemic infl ammatory state, apoCI aggravated LPS-induced atherosclerosis in hyperlipidemic apoE-defi cient mice ( 20 ). We were able to extrapolate these fi ndings to humans by showing that plasma apoCI and apoCI-derived peptides.…”

“…We previously reported that apoCI interacts with different forms of LPS from Salmonella minnesota [i.e., full-length wild-type LPS, and the truncated Re595 LPS, containing the lipid A moiety and some KDO sugars ( 19 )], but more recently we also found that apoCI interacts with different types of LPS from Escherichia coli [i.e . , O55:B5 LPS ( 20 ) and J5 LPS (Berbée and Rensen, unpublished observations)]. ApoCI thus interacts with both fulllength, wild-type LPS and truncated forms of LPS, which indicates that the lipid A/KDO moiety of the LPS molecule contains the crucial elements for interaction with apoCI.…”

Lipopolysaccharide-Induced Proliferation of the Vasa Vasorum in a Rabbit Model of Atherosclerosis as Evaluated by Contrast-Enhanced Ultrasound Imaging and Histology

“…Intravenously injection of endotoxins has been shown to enhance the uptake of oxidized LDLs through increased expression of scavenger receptors [23]. In an apolipoprotein E-deficient mouse model, LPS injections were shown to increase the size of atherosclerotic lesions and were supported by T cell-mediated B cell activation [24] as well as by apolipoprotein CI-induced inflammation [25]. In a rabbit model, systemic inflammation induced by LPS was shown to cause intimal hyperplasia and increased expression of TLR4 and human antigen R [26]; LPS, through TLR4, activated p38 mitogen-activated protein kinase and nuclear factor-κB pathways, and upregulated expression of the Fcα/μ receptor in human macrophages, which promotes the formation of foam cells [27].…”

Marit Westerterp

“…A s an associate research scientist in Alan Tall's group at Columbia University, New York, Marit Westerterp's research has been focused on atherosclerosis and the molecular mechanisms of cholesterol efflux and transport [1][2][3][4][5] -a subject she will continue to pursue in her upcoming role as associate professor at the University of Groningen in the Netherlands.…”