The homozygous RAGE null mouse formed the centerpiece of discoveries during the last cycle of this Program. We demonstrated that RAGE plays critical roles in atheroscierosis in apoE null mice, mediates upregulation of pro-inflammatory and tissue-destructive genes in hypoxia, and mediates loss of cardiac function in the heart upon ischemia/reperfusion (l/R). Multiple novel findings shape the direction of our Program: first, we discovered that the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin homology domain protein family and an effector of RhoGTPases. mDia-1 is essential for RAGE ligand-mediated cellular migration and activation of cdc42/rac-1. New discoveries link mDial to key properties of smooth muscle cells, macrophages and cardiomyocyte signaling. Second, Project 2 has discovered the unanticipated finding that RAGE plays opposing roles in acute vs. chronic hypoxia/ischemia on regulation of Egr-1 in endothelial cells and monocytes/macrophages. Third, Project 1 has discovered that RAGE downregulates ABCG1 and cholesterol efflux to HDL. Fourth, Project 3 has discovered that deletion of mDial is highly protective in the heart in l/R. As a Program, we have shared not merely tools and strategies by virtue of our Core units but, more importantly, we have sought to understand the "big picture" of RAGE signaling. As our data unfold, we recognize that RAGE signaling is not "one size fits all," as new discoveries have uncovered distinct pathways of regulation by the receptor depending on cell type, duration of stress, and specific form of cellular stress. The challenge is to put it together. Toward this end, we have generated novel RAGE- and mDial floxed to probe cell-specific signaling of this axis in atherosclerosis (Project 1), angiogenesis (Project 2) and myocardial infarction (Project 3). Taken together, these discoveries form the basis of a highly innovative and significant set of questions testing RAGE and mDial signaling in vascular dysfunction in diabetic- and non-diabetic cardiovascular pathology. Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program.
Atherosclerosis, peripheral arterial disease and myocardial infarction and its consequences are highly- prevalent diseases in the United States. In subjects with diabetes, the incidence and severity of these disorders is increased. This application focuses on the Receptor for Advanced Glycation Endproducts (RAGE) and its biology in accelerated cardiovascular disease, particularly in diabetes.
|LÃ³pez-DÃez, Raquel; Shekhtman, Alexander; Ramasamy, Ravichandran et al. (2016) Cellular mechanisms and consequences of glycation in atherosclerosis and obesity. Biochim Biophys Acta 1862:2244-2252|
|Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie (2016) The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targets 20:431-46|
|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|
|Thiagarajan, Devi; Ananthakrishnan, Radha; Zhang, Jinghua et al. (2016) Aldose Reductase Acts as a Selective Derepressor of PPARÎ³ and the Retinoic Acid Receptor. Cell Rep 15:181-96|
|Schmidt, Ann Marie (2015) Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease. Vascul Pharmacol 72:1-8|
|Zirpoli, Hylde; Abdillahi, Mariane; Quadri, Nosirudeen et al. (2015) Acute administration of n-3 rich triglyceride emulsions provides cardioprotection in murine models after ischemia-reperfusion. PLoS One 10:e0116274|
|Gao, Minghui; Monian, Prashant; Quadri, Nosirudeen et al. (2015) Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell 59:298-308|
|Schmidt, Ann Marie (2015) The growing problem of obesity: mechanisms, consequences, and therapeutic approaches. Arterioscler Thromb Vasc Biol 35:e19-23|
|Grossin, Nicolas; Auger, Florent; Niquet-Leridon, CÃ©line et al. (2015) Dietary CML-enriched protein induces functional arterial aging in a RAGE-dependent manner in mice. Mol Nutr Food Res 59:927-38|
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