Recent studies indicate that platelet activation plays an important role in all stages of atherosclerotic lesion formation: initiation, progression, stability and thrombosis triggered by plaque rupture. Another event that is critical for the development of atherosclerosis is the generation of biologically active lipids via oxidation of lipoproteins. Considerable evidence has shown that specific oxidized phospholipids are generated in vivo and play a significant role in atherosclerosis. We have recently identified a physiologically relevant mechanism of lipoprotein oxidation and have found that the scavenger receptor CD36 is a major receptor responsible for the recognition of oxidized lipoproteins. A novel structurally conserved family of oxidized choline glycerophospholipids (oxPCcd36) in oxidized lipoproteins serves as high affinity ligands for CD36. oxPCcd36 is generated in vivo, and is enriched in atherosclerotic lesions . oxPCcd36 binds to platelets and induces platelet activation. Scavenger receptors type B (CD36 and SR-BI) appear to be involved. We hypothesized that platelets recognize oxPCcd36 via these receptors and this interaction leads to platelet activation in vivo. This activation could account for the platelet-monocyte and platelet-endothelial cell interaction in the initial stages of atherosclerosis development and for thrombogenicity of the lipid-rich core of plaque. The long-term goal of this proposal is to assess the molecular and cellular mechanisms of platelet interactions with oxPCcd36 and their role in the process of atherogenesis and thrombosis.
The Specific Aims are:
Aim I. To assess the mechanism by which platelet recognize oxPCcd36 and to determine the role of scavenger receptors type B in this process, a) We will characterize the specificity of oxPCcd36 recognition by platelets and receptors involved, b) We will identify the structural motifs of oxidized phospholipids that are essential for the binding to CD36. c) We will determine the molecular requirements for CD36 to recognize oxPCcd36- Aim II. To assess the physiological and pathophysiological consequences of the interaction of oxPCcd36 and platelets as related to platelet adhesion, activation, aggregation, and monocyte recruitment. We will study whether oxPCcd36 induces platelet activation and adhesion as assessed by a variety of assays. We will test whether SR-BI mediated interaction with HDL plays a role in platelet activation. We will test whether platelet activation by oxPCcd36 will induce the formation of platelet-monocyte aggregates. We will further determine whether platelets in such aggregates can activate monocytes.
Aim III. We will seek to obtain evidence that oxPCcd36 can induce platelet activation via CD36 in vivo. We will assess whether oxPCcd36 are able to induce platelet activation and formation of platelet-monocyte aggregates in vivo. We will study the role of scavenger receptors type B in effects of oxPCcd36 in vivo in conditions of hypercholesterolemia. Collectively, the data obtained from this study should provide new information about the role of CD36 in development of atherosclerosis and acute coronary events.
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