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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060901-12
Application #
8301590
Study Section
Special Emphasis Panel (ZHL1-PPG-A (M3))
Program Officer
Olive, Michelle
Project Start
1999-02-01
Project End
2017-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
12
Fiscal Year
2013
Total Cost
$1,477,537
Indirect Cost
$585,483
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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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