Atherosclerosis is a major cause of human cardiovascular disease. Understanding mechanisms that lead to the initiation and progression of atherosclerosis is a current focus of translational research targeting the identification of new pathways for therapeutics. In the last grant cycle, we studied the role of 12/15 lipoxygenase (LO) in regulating monocyte:endothelial interactions in atherosclerosis. We completed the specific aims, and began studying the G protein-coupled receptor G2A, a receptor for two anti-inflammatory eicosanoid products of the 12/15LO family, 13-S-hydroxyoctadecadienoic acid (13SHODE) and 9-S-HODE.
The specific aims of this competitive renewal are directed toward understanding the role of G2A in the initiation, progression and regression of atherosclerosis. Our central hypothesis is that macrophage (mF) G2A serves an anti-inflammatory, protective role in the aortic wall to prevent early events of atherosclerosis by regulating engulfment of apoptotic cells. There are 3 specific aims.
Specific Aim 1 is to determine how G2A regulates apoptotic cell engulfment. We will measure apoptotic cell engulfment, and cholesterol efflux from G2A-deficient mFs.
Specific Aim 2 is to determine the impact of endothelial-specific G2A expression versus lymphocyte-specific G2A expression versus mF-specific G2A expression on atherosclerosis initiation and progression in vivo.
This aim will be accomplished through bone marrow transplantation studies and lymphocyte adoptive transfer studies. Atherosclerosis will be quantified using both en face and aortic root sectioning at various times after western diet feeding.
Specific Aim 3 is to determine if mF-specific expression of G2A promotes regression of atherosclerosis in vivo. We will perform bone marrow transplantation studies to determine whether expression of G2A in mFs promotes regression of atherosclerosis in vivo. These experimental approaches will define the role of the newly discovered anti-inflammatory G2A receptor in contributing to inhibition of atherosclerosis development, and define the importance of G2A in regulating mF-mediated engulfment of apoptotic cells. Defining the roles of G2A in vascular cells with regard to atherogenesis should provide novel strategies for developing new therapies for atherosclerosis prevention or regression. ? ? ?
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