Even after accounting for the major aging-associated diseases, the major factor underlying the enhanced propensity to cardiovascular diseases in human subjects is advancing age itself. Findings uncovered by this Program Project team highlight new concepts in the biology of aging: First, the level and activity of the polyol pathway enzyme aldose reductase (AR) is increased in heart, particularly in endothelial cells and cardiomyocytes. Multiple consequences ensue from upregulation of AR, including generation of diacylglycerol (DAG) and activation of Protein Kinase C (PKC);and production of 3 deoxyglucosone (3-DG) and methylglyoxal (MG), precursors of Advanced Glycation Endproducts (AGEs). Second, accumulation of AGEs and expression of Receptor for Advanced Glycation Endproducts (RAGE) is increased in healthy aged vs. young human and Fischer 344 rat hearts, especially in endothelial cells and cardiomyocytes. The interaction of AGE with RAGE is linked intimately to cellular and tissue perturbation and tissue injury. Our Program is built on the hypothesis that AR primes aged tissues for amplified cardiovascular dysfunction in the basal state. Upon superimposed I/R stress, at least in part via enhanced AGE generation and RAGE expression, increased biochemical and molecular signals amplify injury in the aged heart. We will dissect the influence and intersection of these pathways in aging and I/R stress, and determine the key signaling pathways that modulate expression of pro-inflammatory and prothrombotic genes in basal aging and I/R- stressed cardiovasculature. This proposed Program will consist of three independent but highly integrated projects, led by a team of project leaders with a long history of collaboration in cardiovascular biology. Projects 1 &2 will probe the role of AR pathway and RAGE in the intact heart, respectively. Project 3 will probe AR and RAGE in isolated EC and cardiomyocytes. These studies will address the questions: does basal modulation of AR and RAGE in aging prime the aged heart and, particularly, in endothelial cells and cardiomyocytes, for magnified injury upon I/R stress? Are these pathways, alone, or in combination, novel targets for cardiovascular protection in aging? The proposed Program Project will be supported by three cores: Administrative and Biostatistics;Animal Experimentation and Analysis;and Transgenic Mouse and Animal Management. These endeavors will shed light on mechanisms linking aging to enhanced vulnerability to I/R stress, and, potentially, uncover new therapeutic interventions to suppress I/R injury in the aging cardiovascular system.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-6 (O1))
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Kohanski, Ronald A
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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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 15:181-196
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Schmidt, Ann Marie (2015) Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease. Vascul Pharmacol 72:1-8
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Schmidt, Ann Marie (2015) The growing problem of obesity: mechanisms, consequences, and therapeutic approaches. Arterioscler Thromb Vasc Biol 35:e19-23
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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
Schmidt, Ann Marie (2014) Recent highlights of ATVB: diabetes mellitus. Arterioscler Thromb Vasc Biol 34:954-8
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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