Ischemia limits the ability of a myocardium to generate sufficient high energy phosphates to maintain myocyte viability. Although reperfusion, especially early after the onset of occlusion has revolutionized the treatment of acute myocardial ischemia, beneficial effects are limited by the amount of ischemic damage that occurs prior to reperfusion. In this context, the enhancement of myocardial metabolism during ischemia as means of protecting the myocardium assumes greater importance. In recent years, a variety of metabolic therapies that enhance myocardial metabolism during ischemia have been proposed. They focus on (a) increasing myocardial glycolysis by increasing glucose uptake during ischemia or (b) limiting the inhibitory effects of fatty acids to increase glucose metabolism and flux through pyruvate dehydrogenase (PDH) on reperfusion, and (c) inhibiting sodium and calcium influx pathways during ischemia that deplete high energy phosphates. Recent studies from our laboratory demonstrated a novel metabolic approach of protecting ischemic rat hears by inhibiting aldose reductase, a key regulatory enzyme in the substrate flux via the polyol pathway. This novel intervention limited infarct size and improved function and metabolic recovery after ischemia.
The aim of this proposal research is to delineate the role of aldose reductase protects ischemic myocardium. Specifically, studies will be performed in isolated rat/mice hearts to investigate if (a) ischemia increases aldose reductase activity, and if the hearts over-expressed for aldose reductase exhibit increased ischemic injury in mice transgenic for aldose reductase, the rate of glycolysis and changes in metabolites, the activity of the Na+, K+-ATPase as well as other sodium transporters, and changes in intracellular sodium and calcium during ischemia in aldose reductase inhibited hearts. Biochemical assays will be used to measure enzyme activities and metabolites, while nuclear magnetic resonance (NMR) spectroscopy will be used to measure time dependent changes in intracellular sodium and calcium. The ability to examine the relationship between metabolism and function using biochemical assays and NMR spectroscopy will enhance our understanding of the mechanism by which aldose reductase inhibition protects the myocardium from ischemic injury. Further, this novel approach of protecting the myocardium from ischemic injury, may become a useful therapeutic intervention in treating myocardial infarction in patient.
| 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 |
| 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 |
| 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; 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 |
Showing the most recent 10 out of 32 publications
