Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxidative stress
- 1 September 2010
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 299 (3), C643-C653
- https://doi.org/10.1152/ajpcell.00137.2010
Abstract
Hyperglycemia is an indication of poor outcome for heart attack patients, even for nondiabetic patients with stress-induced hyperglycemia. Previous studies showed that inhibition of aldose reductase, the first and rate-limiting enzyme of the polyol pathway, attenuated contractile dysfunction in diabetic animals, but the mechanism is unclear. We therefore wanted to find out whether the polyol pathway also contributes to acute hyperglycemia-induced cardiac contractile dysfunction, and determine the mechanism involved. Rat hearts were isolated and retrogradely perfused with Krebs buffer containing either normal or high concentrations of glucose for 2 h. Short exposure to high-glucose medium led to contractile dysfunction as indicated by decreased −dP/dtmax, as well as elevation in left ventricular end-diastolic pressure. Cardiomyocytes incubated in high-glucose medium showed abnormal Ca2+ signaling, most likely because of decreased activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) inactivated by oxidative stress. Inhibition of aldose reductase or sorbitol dehydrogenase, the second enzyme in the polyol pathway, ameliorated contractile dysfunction, attenuated oxidative stress, and normalized Ca2+ signaling and SERCA activity caused by high glucose, indicating that the polyol pathway is the major contributor to acute hyperglycemia-induced oxidative stress leading to the inactivation of SERCA and contractile dysfunction.Keywords
This publication has 68 references indexed in Scilit:
- H2O2-induced left ventricular dysfunction in isolated working rat hearts is independent of calcium accumulationJournal of Molecular and Cellular Cardiology, 2008
- Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat heartsCardiovascular Diabetology, 2008
- Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca2+ ATPase in diabetic pig aortaFree Radical Biology & Medicine, 2008
- Polyol pathway mediates iron-induced oxidative injury in ischemic–reperfused rat heartFree Radical Biology & Medicine, 2008
- Role of Nitric Oxide in Regulating Aldose Reductase Activation in the Ischemic HeartJournal of Biological Chemistry, 2008
- Testosterone protects rat hearts against ischaemic insults by enhancing the effects of α1‐adrenoceptor stimulationBritish Journal of Pharmacology, 2008
- High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migrationJournal of Molecular and Cellular Cardiology, 2008
- Chronic intermittent hypoxia alters Ca2+handling in rat cardiomyocytes by augmented Na+/Ca2+exchange and ryanodine receptor activities in ischemia-reperfusionAmerican Journal of Physiology-Cell Physiology, 2007
- A possible role of noradrenaline in the development of myocardial infarctionAmerican Heart Journal, 1978
- New type of cardiomyopathy associated with diabetic glomerulosclerosisThe American Journal of Cardiology, 1972