Accelerated atherosclerosis is a major cause of morbidity and mortality in subjects with diabetes. Extensive evidence using pharmacological antagonists and genetically modified mice points to key roles for the Receptor for Advanced Glycation Endproducts in diabetic and non-diabetic atherosclerosis. We have discovered that homozygous RAGE null mice display significant reduction In atherosclerosis in the apoE null background, both in the non-diabetic and diabetic state. In parallel, significantly reduced vascular inflammation accompanies the benefits of RAGE deletion. The interaction of the RAGE cytoplasmic domain with mDial, a formin family molecule, highlights novel insights Into the mechanisms by which RAGE signals. Major discoveries that form the basis of this Project include that in macrophages, RAGE markedly suppresses transcription and translation of the cholesterol transporter ABCGI, and, thereby, greatly reduces cholesterol efflux to HDL. In SMCs, RAGE ligands stimulate proliferation and migration In a manner dependent on mDia-1 and signaling through glycogen synthase kinase-n (GSK-3n) In this application, we will employ newly-developed two sets of novel floxed mice in which we may delete RAGE specifically in SMCs or monocytes/macrophages to probe in-depth the mechanisms by RAGE and mDial contribute to accelerated atherosclerosis. Project 1 is integrally linked within the Program. Together the three projects will probe the intricacies of RAGE signaling, recognizing that some processes appear dependent vs. independent of mDial Project 1 collaborates with Project 2 on RAGE &glyoxalase!;and Project 1 collaborates with Project 3 on opposing roles of RAGE on regulation of Ser9 phosphorylation of GSK-SD and cell fate. Project 1 shares findings from Affymetrix gene array studies with Projects 2&3 to create integrated pathways by which RAGE signaling regulates cardiovascular stress. Project 1 uses all three Cores of the Program during all five years.
In subjects with diabetes, the incidence and severity of atherosclerosis is increased. The Receptor for Advanced Glycation Endproducts (RAGE) and its ligand families are implicated in accelerated atherosclerosis in both the non-diabetic and diabetic state. Dissecting the interplay of inflammatory - vascular cell interplay in the context of RAGE is critical to unraveling novel strategies for therapeutic intervention in atherosclerosis.
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