Peripheral arterial disease (PAD) is a major complication of diabetes and is a leading cause of amputations of digits or limbs. My laboratory has focused for the past 15 years on the molecular regulation of genes in hypoxic stress. In the previous cycle, three major discoveries linked RAGE to regulation of acute responses to hypoxia: First, in cultured endothelial cells and monocytes/macrophages, acute exposure to hypoxia resulted in rapid release of AGE-reactive epitopes within minutes of hypoxic stress. Second, in the intact heart and in primary murine aortic and human aoilic endothelial cells, RAGE regulated rapid upregulation of Egr-1 in a manner suppressed by deletion or knockdown of RAGE and by aminoguanidine, an AGE inhibitor. Third, in collaboration with Project 1, we showed that monocytes/macrophages devoid of RAGE orthe RAGE cytoplasmic domain binding partner, diaphanous-1 or mDia-1, did not upregulate Egr-1 in acute hypoxia. To address the diabetes-relevant implications of these findings, we employed an in vivo model of hind limb ischemia induced by unilateral femoral artery ligation. Diabetes significantly impairs vascular repair mechanisms in this model. Our preliminary data reveal a fascinating and unexpected switch in RAGE signaling in acute vs. chronic oxygen deprivation ... whereas RAGE signaling upregulates Egr-1 in acute hypoxia, in hind limb ischemia, particularly in diabetes, RAGE suppresses adaptive induction of Egr-1 and, in parallel, reduces angiogenesis and blood flow recovery. In this application, we will probe the effects of specific deletion of RAGE in either monocytes/macrophages or endothelial cells to dissect the mechanisms by which RAGE action suppresses angiogenesis and blood flow recovery. Together with Projects 1&3, we will discern the fine-tuning mechanisms by which RAGE acts in common cardiovascular stresses, as all three Projects will use Affymetrix arrays to develop an integrated picture of RAGE signaling in distinct cell types and situations. We will use all three Cores in all five years ofthe Program.

Public Health Relevance

Peripheral arterial disease is associated with increased morbidity and mortality, particularly in subjects with diabetes. This Project focuses on the Receptor for Advanced Glycation Endproducts (RAGE) and its biology in this disorder. Understanding the role of RAGE in the vascular and inflammatory response to peripheral arterial disease is essential for the design of new therapies for diabetic vascular disease.

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New York University
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Schmidt, Ann Marie (2014) Skin autofluorescence, 5-year mortality, and cardiovascular events in peripheral arterial disease: all that glitters is surely not gold. Arterioscler Thromb Vasc Biol 34:697-9
Song, Fei; Hurtado del Pozo, Carmen; Rosario, Rosa et al. (2014) RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice. Diabetes 63:1948-65
Vedantham, Srinivasan; Thiagarajan, Devi; Ananthakrishnan, Radha et al. (2014) Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals. Diabetes 63:761-74
Schmidt, Ann Marie (2014) Recent highlights of ATVB: diabetes mellitus. Arterioscler Thromb Vasc Biol 34:954-8
Manigrasso, Michaele B; Juranek, Judyta; Ramasamy, Ravichandran et al. (2014) Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab 25:15-22
Kong, Linghua; Shen, Xiaoping; Lin, Lili et al. (2013) PKC* promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE null mice. Arterioscler Thromb Vasc Biol 33:1779-87
Tekabe, Yared; Luma, Joane; Li, Qing et al. (2012) Imaging of receptors for advanced glycation end products in experimental myocardial ischemia and reperfusion injury. JACC Cardiovasc Imaging 5:59-67
Toure, Fatouma; Fritz, Gunter; Li, Qing et al. (2012) Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways. Circ Res 110:1279-93
Vedantham, Srinivasan; Noh, HyeLim; Ananthakrishnan, Radha et al. (2011) Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice. Arterioscler Thromb Vasc Biol 31:1805-13
Hofmann Bowman, Marion A; Fedson, Savitri; Schmidt, Ann Marie (2011) Advanced glycation end products in diabetic cardiomyopathy: an alternative hypothesis. J Heart Lung Transplant 30:1303; discussion 1303-4

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