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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1481.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Dietary Cholesterol Plays a Role in CD36-Mediated Atherogenesis in LDLR-Knockout Mice

David J. Kennedy; Sai D. Kuchibhotla; Ella Guy; Young Mi Park; George Nimako; DiFernando Vanegas; Richard E. Morton; Maria Febbraio

From the Department of Cell Biology (D.J.K., S.D.K., Y.M.P., G.N., D.V., R.E.M., M.F.), Cleveland Clinic, Ohio; and the Department of Medicine (E.G.), Weill Medical College of Cornell University, New York.

Correspondence to Maria Febbraio, PhD, Department of Cell Biology, NC-10, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195. E-mail febbram{at}ccf.org

Objective— CD36 has been shown to play a role in atherosclerosis in the apolipoprotein E-knockout (apoE^o) mouse. We observed no difference in aortic lesion area between Western diet (WD)-fed LDLR^o and LDLR^o/CD36^o mice. The objective was to understand the mechanism of CD36-dependent atherogenesis.

Methods and Results— ApoE^o mice transplanted with bone marrow from LDLR^o/CD36^o mice had significantly less aortic lesion compared with those transplanted with LDLR^o marrow. Reciprocal macrophage transfer into hyperlipidemic apoE^o and LDLR^o animals showed that foam cell formation induced by in vivo modified lipoproteins was dependent on the lipoprotein, not macrophage type. LDLR^o and LDLR^o/CD36^o mice were fed a cholesterol-enriched diet (HC), and we observed significant lesion inhibition in LDLR^o/CD36^o mice. LDL/plasma isolated from HC-fed LDLR^o mice induced significantly greater jnk phosphorylation, cytokine release, and reactive oxygen species secretion than LDL/plasma from WD-fed LDLR^o mice, and this was CD36-dependent. HC-fed LDLR^o mice had higher circulating levels of cytokines than WD-fed mice.

Conclusions— These data support the hypothesis that CD36-dependent atherogenesis is contingent on a proinflammatory milieu that promotes the creation of specific CD36 ligands, not solely hypercholesterolemia, and may explain the greater degree/accelerated rate of atherosclerosis observed in syndromes associated with inflammatory risk.

In the LDLR knockout mouse model of atherogenesis, dietary cholesterol played a role in CD36-dependent lesion burden. Addition of cholesterol resulted in increased inflammation and release of reactive oxygen species by macrophages, which was abrogated in the absence of CD36. A proinflammatory milieu may be essential to creation of CD36-specific proatherogenic ligands.

Key Words: CD36 • atherosclerosis • murine models • inflammation • scavenger receptor