Aging in human subjects is associated with heightened susceptibility to injury triggered by ischemia/reperfusion (I/R). Fundamental metabolic and biochemical changes occur in aging tissues in the basal state, and consequent to I/R. Aged human and Fischer 344 rat hearts display increased accumulation of Advanced Glycation Endproducts (AGEs), the products of nonenzymatic glycation/oxidation of proteins/lipids. AGEs may impart """"""""gain of function"""""""" in the tissues by virtue of their ability to trigger signaling pathways, via Receptor for AGE (RAGE). In human aging, in the absence of overt cardiovascular disease or diabetes, increased expression/activity of the key polyol pathway enzyme aldose reductase (AR) occurs, leading to multiple metabolic disturbances, including generation of methylglyoxal (MG) and 3- deoxyglucosone (3-DG), precursors of AGEs. Aged human hearts, in the absence of cardiovascular disease or risk factors, display increased expression of RAGE antigen vs. young hearts. Our preliminary data reveal that myocardium of aged Fischer 344 rats (age, 24 mos), displays increased RAGE antigen compared to young rats (age, 4 months), particularly in endothelial cells (EC) and cardiomyocytes. Pharmacological blockade of RAGE in aged Fischer 344 rats attenuates I/R injury in the isolated perfused heart. Thus, we hypothesize that in aging, accumulation of AGEs upregulates expression of RAGE, thereby establishing basal dysfunction. Upon superimposed I/R, augmented ligand-RAGE mechanisms set the stage for enhanced biochemical and inflammatory stress and impairment in metabolism. Together, these forces converge to magnify I/R injury. We will test these concepts in aged Fischer 344 rats and RAGE mutant mice. These studies will be built on the premise that pharmacological blockade of RAGE may represent a potent strategy for the prevention of age-related cardiovascular dysfunction. Project 2 is closely linked to Projects 1&3, as each studies aging-linked enhanced vulnerability to I/R in the intact heart and isolated EC and cardiomyocytes, respectively. Project 2 shares mouse/rat models with Projects 1 and 3. Project 2 will utilize all three Cores of the Program Project during all five years of the grant.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
7P01AG026467-04
Application #
8235873
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
4
Fiscal Year
2011
Total Cost
$214,000
Indirect Cost
Name
New York University
Department
Type
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Thiagarajan, Devi; Vedantham, Srinivasan; Ananthakrishnan, Radha et al. (2016) Mechanisms of transcription factor acetylation and consequences in hearts. Biochim Biophys Acta 1862:2221-2231
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
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
Schmidt, Ann Marie (2015) Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease. Vascul Pharmacol 72:1-8
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
Schmidt, Ann Marie (2014) Recent highlights of ATVB: diabetes mellitus. Arterioscler Thromb Vasc Biol 34:954-8
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) 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
Bao, Li; Taskin, Eylem; Foster, Monique et al. (2013) Alterations in ventricular K(ATP) channel properties during aging. Aging Cell 12:167-76

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