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

Objective-CD36 has been shown to play a role in atherosclerosis in the apolipoprotein E-knockout (apoE degrees) mouse. We observed no difference in aortic lesion area between Western diet (WD)-fed LDLR degrees and LDLR degrees/CD36 degrees mice. The objective was to understand the mechanism of CD36-dependent atherogenesis. Methods and Results-ApoE degrees mice transplanted with bone marrow from LDLR degrees/CD36 degrees mice had significantly less aortic lesion compared with those transplanted with LDLR degrees marrow. Reciprocal macrophage transfer into hyperlipidemic apoEo and LDLR degrees animals showed that foam cell formation induced by in vivo modified lipoproteins was dependent on the lipoprotein, not macrophage type. LDLR degrees and LDLR degrees/CD36 degrees mice were fed a cholesterol-enriched diet (HC), and we observed significant lesion inhibition in LDLR degrees/CD36 degrees mice. LDL/plasma isolated from HC-fed LDLR degrees mice induced significantly greater jnk phosphorylation, cytokine release, and reactive oxygen species secretion than LDL/plasma from WD-fed LDLR degrees mice, and this was CD36-dependent. HC-fed LDLR degrees 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. (Arterioscler Thromb Vasc Biol. 2009; 29: 1481-1487.)