The scavenger receptor CD36 participates a diverse array of physiological processes. In addition to its role in recognition of oxidized low density lipoprotein (oxLDL), lipid accumulation and foam cell formation, the scavenger receptor functions of CD36 have been linked to recognition of senescent and apoptotic cells, and the delivery of ligands within oxLDL into cells. We recently identified a novel family of oxidized choline glycerol-phospholipids that serve as high affinity ligands for CD36 (oxPCCD36). A conserved structural motif that supports high affinity interactions with the oxLDL binding site of CD36 was defined: a truncated sn-2 acyl group that incorporates a terminal y-hydroxy (or oxo) and a,B unsaturated carbonyl. In preliminary studies we show that plasma levels of oxPCCD36 are strongly correlated with quantitative measures (via IVUS) of coronary artery atherosclerotic burden. We also show that it is not non-oxidized phosphatidyl serine (PS), but rather, oxidized PS species (oxPS), that promote macrophage recognition of apoptotic cells via CD36. Little is known about structural or biochemical factors involved in formation of phospholipid CD36 ligands, or CD36-lipid ligand interactions. Moreover, the physiological relevance of these novel bioactive oxidized phospholipids is unknown. The overall goals of this project are to define the structures, biochemical properties, mechanisms of formation/decay, and critical receptor-ligand interactions of specific oxidized phospholipid ligands of CD36.
The Specific Aims are: 1) To identify endogenous phospholipid oxidation products that serve as high affinity ligands for the macrophage scavenger receptor CD36 and define critical structure-function relationships for specific oxidized phospholipids and lipid-receptor complexes implicated both in phagocytosis of apoptotic cells and in atherogenesis. 2) To define the clinical relevance of specific oxPC and oxPS species in cardiovascular disease, and to identify pathways involved in their in vivo formation and decay/metabolism.
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