Diabetic patients, both Type 1 and 2 display both increased incidence of cardiovascular disease, and complications of myocardial infarction and heart failure. Altered cardiac function, metabolism of glucose and fatty acids, and sodium homeostasis have been demonstrated in both types of diabetes. Altered glucose metabolism, in particular, flux of glucose via the polyol pathway may be responsible, in part, for the enhanced vulnerability of diabetic myocardium to ischemic injury. In polyol pathway, glucose is reduced to sorbitol by aldose reductase (AR) and subsequently oxidized to fructose by sorbitol dehydrogenase (SDH). We have demonstrated that flux via the polyol pathway is partly responsible for impaired myocardial glycolysis and energy production. When diabetic hearts are subjected to ischemia, the ability to generate sufficient high-energy phosphates for maintaining myocyte viability and for 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 context, our preliminary data demonstrate increased AR and SDH activities in both type 1 and Type 2 diabetic rat hearts and that pharmacological inhibition of AR normalized glycolysis and Na+,K+-ATPase activity via protein kinase C-B Induction of ischemia further increases AR and SDH activity in diabetic hearts and is associated with increased myocardial ischemic injury and poor functional recovery on reperfusion. Inhibition of the polyol pathway reduced ischemic injury, attenuated changes in intracellular sodium homeostasis, and improved functional and metabolic recovery after ischemia in diabetic hearts. These data lead to the hypothesis that in Type 1 and 2 diabetes, increased activity of polyol pathway enzymes AR and SDH increases myocardial vulnerability to ischemic injury, and that this can be attenuated by polyol pathway inhibitors. Mechanisms by which diabetes increases myocardial AR activity, how augmented AR activity in diabetes and ischemia acts to increase myocardial damage, and impairs sodium homeostasis and energy metabolism will be investigated. Type 1 and Type 2 diabetic and non-diabetic littermate rats, as well as transgenic mice, will be used to test our hypothesis and elucidate mechanisms using NMR spectroscopy, biochemical, and molecular techniques. The proposed studies will provide a rationale for the use of polyol pathway inhibitors as an adjunctive therapeutic intervention for treating diabetic patients with myocardial infarction.
| 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 |
| 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 |
| Ananthakrishnan, Radha; Kaneko, Michiyo; Hwang, Yuying C et al. (2009) Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 296:H333-41 |
| Bucciarelli, Loredana G; Ananthakrishnan, Radha; Hwang, Yuying C et al. (2008) RAGE and modulation of ischemic injury in the diabetic myocardium. Diabetes 57:1941-51 |
| Li, Qing; Hwang, Yuying C; Ananthakrishnan, Radha et al. (2008) Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts. Cardiovasc Diabetol 7:33 |
| Aleshin, Alexey; Ananthakrishnan, Radha; Li, Qing et al. (2008) RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model. Am J Physiol Heart Circ Physiol 294:H1823-32 |
| Bucciarelli, Loredana G; Kaneko, Michiyo; Ananthakrishnan, Radha et al. (2006) Receptor for advanced-glycation end products: key modulator of myocardial ischemic injury. Circulation 113:1226-34 |
| Hwang, Yuying C; Shaw, Sean; Kaneko, Michiyo et al. (2005) Aldose reductase pathway mediates JAK-STAT signaling: a novel axis in myocardial ischemic injury. FASEB J 19:795-7 |
| Ananthakrishnan, Radha; Hallam, Kellie; Li, Qing et al. (2005) JAK-STAT pathway in cardiac ischemic stress. Vascul Pharmacol 43:353-6 |
Showing the most recent 10 out of 15 publications
