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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Schmidt, Ann Marie (2018) Highlighting Diabetes Mellitus: The Epidemic Continues. Arterioscler Thromb Vasc Biol 38:e1-e8
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Lee, Gloria; Kranzler, Jay D; Ramasamy, Ravichandran et al. (2018) Training scientists as future industry leaders: teaching translational science from an industry executive's perspective. J Transl Sci 4:
Schmidt, Ann Marie (2017) 2016ATVBPlenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis an Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage. Arterioscler Thromb Vasc Biol 37:613-621
López-Díez, Raquel; Shen, Xiaoping; Daffu, Gurdip et al. (2017) Ager Deletion Enhances Ischemic Muscle Inflammation, Angiogenesis, and Blood Flow Recovery in Diabetic Mice. Arterioscler Thromb Vasc Biol 37:1536-1547
Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie (2017) Glycation & the RAGE axis: targeting signal transduction through DIAPH1. Expert Rev Proteomics 14:147-156
Senatus, Laura M; Schmidt, Ann Marie (2017) The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases. Front Genet 8:187
López-Díez, Raquel; Shekhtman, Alexander; Ramasamy, Ravichandran et al. (2016) Cellular mechanisms and consequences of glycation in atherosclerosis and obesity. Biochim Biophys Acta 1862:2244-2252
Thiagarajan, Devi; Vedantham, Srinivasan; Ananthakrishnan, Radha et al. (2016) Mechanisms of transcription factor acetylation and consequences in hearts. Biochim Biophys Acta 1862:2221-2231
Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek et al. (2016) Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction. Sci Rep 6:22450

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