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.
|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; 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|
|Schmidt, Ann Marie (2017) 2016 ATVB Plenary 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|
|Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek et al. (2016) Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction. Sci Rep 6:22450|
|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|
|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; Ananthakrishnan, Radha; Zhang, Jinghua et al. (2016) Aldose Reductase Acts as a Selective Derepressor of PPAR? and the Retinoic Acid Receptor. Cell Rep 15:181-96|
|Litwinoff, Ems; Hurtado Del Pozo, C; Ramasamy, R et al. (2015) Emerging Targets for Therapeutic Development in Diabetes and Its Complications: The RAGE Signaling Pathway. Clin Pharmacol Ther 98:135-44|
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