Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxidative stress.

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/dt(max), 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.

• Authors: Wai Ho Tang, Wing Tim Cheng, Gennadi M Kravtsov, Xiao Yong Tong, Xiu Yun Hou, Sookja K Chung, Stephen Sum Man Chung
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 299 Issue 3 Pg. C643-53 (Sep 2010) ISSN: 1522-1563 [Electronic] United States
• PMID: 20573996 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Atp2a2 protein, rat
• Superoxides
• Peroxynitrous Acid
• Lactic Acid
• Tyrosine
• Pyruvic Acid
• Aldehyde Reductase
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Glutathione
• Glucose

Topics

• Acute Disease
• Aldehyde Reductase (physiology)
• Animals
• Calcium Signaling
• Glucose (pharmacology)
• Glutathione (metabolism)
• Heart (physiopathology)
• Hyperglycemia (metabolism, physiopathology)
• In Vitro Techniques
• Lactic Acid (metabolism)
• Male
• Myocardial Contraction
• Myocardium (metabolism)
• Oxidation-Reduction
• Oxidative Stress
• Perfusion
• Peroxynitrous Acid (metabolism)
• Pyruvic Acid (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Signal Transduction
• Superoxides (metabolism)
• Tyrosine (metabolism)