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.