Aging human subjects display increased incidence of cardiovascular disease and complications of myocardial infarction and heart failure. We have demonstrated that flux via the polyol pathway is partly responsible for impaired myocardial glycolysis and energy production. When hearts from aged rats are subjected to ischemia, the ability to generate sufficient high energy phosphates for maintaining myocyte viability and sodium homeostasis is severely compromised. Our work, as well as that of others, has shown that enhancement of glycolytic metabolism during ischemia is a feasible approach to maintain myocyte viability, energy metabolism and sodium homeostasis. In this revised application, we show that in human aging, that is, without superimposed cardiovascular disease or diabetes, and in aged Fischer 344 rats, expression and activity of aldose reductase (AR) is increased in the heart. Induction of ischemia further increases AR activity in aged hearts, and is associated with increased myocardial ischemic injury and poor functional recovery on reperfusion. Inhibition of the polyol pathway (AR) or the next enzyme in the pathway, sorbitol dehydrogenase (SDH) reduced ischemic injury, attenuated changes in intracellular sodium homeostasis, and improved functional and metabolic recovery after ischemia in aged hearts. Thus, we hypothesize that in aging, increased activity of the polyol pathway enzyme AR increases myocardial vulnerability to ischemic injury, and that this can be attenuated by polyol pathway inhibitors. The proposed studies will probe the mechanisms by which aging increases myocardial polyol pathway activity, and how this augmented activity in aging and ischemia acts to increase myocardial damage Distinct strategies including pharmacological inhibitors of AR and SDH, Fischer 344 rats, and human AR expressing transgenic mice will be employed to test these concepts. Further, to enhance understanding of SDH in aging in the heart, SDH null mice will be bred into the transgenic mouse background in which human-relevant levels of AR are expressing. We will utilize NMR spectroscopy, biochemical, and molecular techniques in our experiments. Project 1 is closely linked to Projects 2&3, as each studies aging-linked enhanced vulnerability to I/R stress in vascular cells and cardiomyocytes. Project 1 shares mouse/rat models with Projects 2 and 3. Project 1 will utilize all three Cores of the Program Project during all five years of the grant.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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New York University
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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 15:181-96
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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