Marit Westerterp

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 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.

Objective— The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden ( E3L ) mice with a humanized lipoprotein profile. Methods and Results— E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (+43%; P E3L and CETP.E3L mice ( P CETP.E3L mice had reduced capacity (−39%; P E3L mice. After 19 weeks on the Western-type diet, CETP.E3L mice showed a 7.0-fold increased atherosclerotic lesion area in the aortic root compared with E3L mice ( P Conclusions— CETP expression in E3L mice shifts the distribution of cholesterol from HDL to VLDL/LDL, reduces plasma-mediated SR-BI–dependent cholesterol efflux, and represents a clear pro-atherogenic factor in E3L mice. We anticipate that the CETP.E3L mouse will be a valuable model for the preclinical evaluation of HDL-raising interventions on atherosclerosis development.