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Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts

By Qing Li, Yuying C Hwang, Radha Ananthakrishnan, Peter J Oates, Dennis Guberski and Ravichandran Ramasamy

Abstract

We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients

Topics: Original Investigation
Publisher: BioMed Central
OAI identifier: oai:pubmedcentral.nih.gov:2584021
Provided by: PubMed Central

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Citations

  1. (1986). Activation of human erythrocyte, brain, aorta, muscle, and occular tissue aldose reductase. Metabolism
  2. Aldose reductase and vascular stress.
  3. (1997). Aldose reductase inhibition protects diabetic and non-diabetic rat hearts from ischemic injury. Diabetes
  4. (2006). Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism.
  5. (1996). AM: Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-1 experience.
  6. (2000). Anverse P: Myocardial cell death in human diabetes. Circ Res
  7. (1999). Attenuation of ischemia induced increases in sodium and calcium by an aldose reductase inhibitor zopolrestat. Cardiovasc Res
  8. (2005). BM: Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes
  9. (1990). Cala PM: Na-H exchange in myocardium: effects of hypoxia and acidification on Na and Ca.
  10. (1997). DN: Glucose-specific regulation of aldose reductase in Capan-1 human pancreatic duct cells in vitro.
  11. (1993). E: Mechanism of preconditioning: ionic alterations. Circ Res
  12. (2005). Ergul A: Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice.
  13. (2007). Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats. Cardiovasc Diabetol
  14. (2004). Flyvbjerg A: Ischemic preconditioning does not protect the heart in obese and lean animal models of Type 2 diabetes. Diabetologia
  15. (1997). Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor. Curr Eye Res
  16. (2004). Guberski DL: The BBZDR/Wor rat model for investigating the complications of type 2 diabetes mellitus.
  17. (2007). Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats. Am J Physiol Heart Circ Physiol
  18. (2001). Ido Y: Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes.
  19. (1984). Increased congestive heart failure after myocardial infarction of moderate extent in patients with diabetes mellitus. Am Heart J
  20. (1999). Inhibition of Na+-H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury: insight into altered susceptibility of diabetic hearts to ischemic injury.
  21. (2004). Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Cardiovasc Res
  22. (1995). Ischemic preconditioning stimulates sodium and proton transport in the isolated rat heart.
  23. (2004). JC: Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart.
  24. (1992). JR: Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+. Kidney Int
  25. (1994). KH: An anion binding site in human aldose reductase: Mechanistic implications for the binding of citrate, cacodylate, and glucose-6-phosphate. Biochemistry
  26. (1995). KH: Human aldose reductase: pK of tyrosine 48 reveals the preferred ionization state for catalysis and inhibition. Biochemistry
  27. (1995). KH: Human aldose reductase: subtle effects revealed by rapid kinetic studies of the C298A mutant enzyme. Biochemistry
  28. (1985). Kinoshita JH: Role of aldose reductase in the development of diabetes associated complications.
  29. (2001). Kukreja RC: Mitogen-activated protein kinases mediate heat shock induced delayed protection in mouse heart.
  30. (1990). London RE: Correlation between cystolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res
  31. (2000). MB: Increased H2O2, vascular endothelial growth factor and receptors in the retina of the BBZ/Wor diabetic rat. Free Radical Biology Medicine
  32. (1994). Myocardial infarct size and mortality in patients with non- insulin-dependent diabetes mellitus.
  33. (1995). O'Neill WW: Predictors of in-hospital and 6-minth outcome after acute myocardial infarction in the reperfusion era: the primary angioplasty in myocardial infarction (PAMI) trial.
  34. (2005). PJ: A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes. Experimental Neurology
  35. (2000). PJ: Aldose reductase inhibition alone or combined with an adenosine A(3) agonist reduces ischemic myocardial injury. Am J Physiol Heart Circ Physiol
  36. (2002). Ramasamy R: Aldose reductase activation is a key component of myocardial response to ischemia. FASEB
  37. (1998). Ramasamy R: Aldose reductase inhibition improves the altered glucose metabolism of isolated diabetic rat hearts.
  38. (2004). Ramasamy R: Central role for aldose reductase pathway in myocardial ischemic injury.
  39. (1995). Regan TJ: Cardiac consequences of diabetes mellitus. Clin Cardiol
  40. (2000). RH: Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA
  41. (1991). Ronfeld RA: Pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, in normal and diabetic rats. Pharmaceut Res
  42. (1998). S: Metabolic effects of aldose reductase inhibition during low-flow ischemia and reperfusion.
  43. (1993). SA: Aldose reductase inhibitors: an approach to the treatment of diabetic nerve damage. Diabetes Metab Rev
  44. (2003). Sorbitol dehydrogenase: A novel target for adjunctive protection of ischemic myocardium.
  45. (2001). SR: Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4. Am J Physiol Heart Circ Physiol
  46. (2001). SR: Protection of ischemic hearts perfused with an anion exchange inhibitor, DIDS, is associated with beneficial changes in substrate metabolism. Cardiovasc Res
  47. (1973). The polyol pathway and the complications of diabetes.
  48. (1988). The role of aldose reductase in the development of diabetic complications. Med Res Rev
  49. (1993). Tilton RG: Hyperglycemic pseudohypoxia and diabetic complications. Diabetes
  50. (1974). WB: Morbidity and mortality in the Framingham population: sixteenyear followup study. Diabetes
  51. (2000). Yorek BM: A comparison of diabetic polyneuropathy in Type 2 diabetic BBZDR/Wor rats and in Type 1 diabetic BB/Wor rats. Diabetologia
  52. (1990). Zucker diabetic fatty rat asa model for non-insulin-dependent diabetes mellitus. ILAR News

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