CD36 is a broadly expressed transmembrane glycoprotein capable of many functions, including those carried out by scavenger receptors and others, such as adhesion ligand internalization, fatty acid transport and cell signaling. Previous work in our lab demonstrated an important role for CD36 in atherogenesis: absence of CD36 in the ApoE null background resulted in a 70 percent inhibition of aortic tree lesions. In this application, we will determine the mechanism of atheroprotection afforded by CD36 deficiency by characterizing the role of CD36 in lesion progression. and in models of atherogenesis in which insulin resistance plays a role. We hypothesize that continued progression of lesions may be due to uptake of more extensively oxidized LDL by SR-Al/Il, and we will test this hypothesis by assessment of lesion development in ApoE/CD36/SR-AI/II triple null mice. Alternatively. angiogenesis or efflux may play a role in lesion progression, and we will quantitate vessel number and investigate efflux protein expression. We will characterize the impact of the differential functions of CD36 on atherosclerosis b hematopoietic stem cell transplant and conditional cell/tissue ablation of CD36 using CRELox technology. To further investigate the mechanism of atheroprotection in the absence of CD36, we will characterize cholesterol efflux pathways in isolated macrophages from wild type and CD36 null mice, and determine the impact of prior lipid loading, and PPAR-gamma agonists. These studies will be complemented by in vivo assessment of atherosclerotic lesion development after PPAR-y treatment in LDLR/CD36 null and Apo E/CD36 null mice, and in both atherogenic backgrounds after transfer of CD36 stem cells. In this way. the contribution of macrophage CD36 to atherogenesis as compared to fat, endothelial cell and muscle CD36 can be assessed, and specific mechanisms delineated. We believe these approaches will enable us to understand the pathogenesis of foam cell and atheroma development, and lead to novel therapeutic strategies.
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