Recanalization therapy remains the most effective way for treatment of evolving myocardial infarction and thereby salvaging jeopardized tissue. However, the efficacy of reperfusion in limiting infarction and improving recovery of contractile function depends on the amount of irreversible damage occurring prior to initiating reperfusion and is related to failure of energy production to meet the basal needs of the injured myocardium. In recent years, a variety of metabolic therapies that enhance myocardial metabolism and attenuate changes in sodium and calcium homeostasis during ischemia have been proposed. However, much remains to be learned about the metabolic flux that are active under ischemic conditions and may trigger pathways that influence ischemic injury. In this context, our studies, funded by the grant HL61783, demonstrated that aldose reductase (a key regulatory enzyme in the substrate flux via polyol pathway) is activated in ischemic hearts, and that inhibiting flux via aldose reductase reduced ischemic injury, improved functional recovery and energy homeostasis, and was associated with attenuation of the rise in cytosolic NADH/NAD+, intracellular sodium and calcium.
The aim of the proposed research is to delineate the mechanisms by which increased aldose reductase activity mediates ischemic injury. Recent studies in the literature suggests that mitochondrial functional recovery and signal transduction by JAK-STAT pathway due to changes in NADH/NAD+ are two key components that are likely to determine the survival of myocyte during reperfusion. Preliminary data shown here suggest that aldose reductase activation impairs mitochondrial function and signals activation of STATs involved in cell death. These data lead to the hypotheses that increased expression of aldose reductase increases ischemic injury and that the increased activity of aldose reductase mediates ischemic injury, in part, by influencing mitochondrial function and signal transduction (specifically JAK-STAT signaling). Mechanisms by which aldose reductase impairs mitochondrial function and induces JAK-STAT activation will be investigated. Strategies to determine mechanisms include the use of pharmacological inhibitors of aldose reductase in rats, (b) mice overexpressing human aldose reductase, (c) mice homozygously null for aldose reductase. The data from these studies will help understand the mechanisms by which aldose reductase mediates ischemic injury. Furthermore, these studies will likely lead to the use of aldose reductase inhibitors as therapeutic adjuncts in treating evolving myocardial infarction in patients.
| 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 |
| 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 |
| 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 |
| Abdillahi, Mariane; Ananthakrishnan, Radha; Vedantham, Srinivasan et al. (2012) Aldose reductase modulates cardiac glycogen synthase kinase-3? phosphorylation during ischemia-reperfusion. Am J Physiol Heart Circ Physiol 303:H297-308 |
| Vedantham, Srinivasan; Ananthakrishnan, Radha; Schmidt, Ann Marie et al. (2012) Aldose reductase, oxidative stress and diabetic cardiovascular complications. Cardiovasc Hematol Agents Med Chem 10:234-40 |
| Abel, E Dale; O'Shea, Karen M; Ramasamy, Ravichandran (2012) Insulin resistance: metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol 32:2068-76 |
| 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 |
| Ananthakrishnan, Radha; Li, Qing; Gomes, Teodoro et al. (2011) Aldose reductase pathway contributes to vulnerability of aging myocardium to ischemic injury. Exp Gerontol 46:762-7 |
| Ramasamy, Ravichandran; Goldberg, Ira J (2010) Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model. Circ Res 106:1449-58 |
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