Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxidative stress.
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.
Tang
Wai Ho
WH
Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Cheng
Wing Tim
WT
Kravtsov
Gennadi M
GM
Tong
Xiao Yong
XY
Hou
Xiu Yun
XY
Chung
Sookja K
SK
Chung
Stephen Sum Man
SS
D000208:Acute Disease; D000449:Aldehyde Reductase / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010477:Perfusion; D030421:Peroxynitrous Acid / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
C506948:Atp2a2 protein, rat; D013481:Superoxides; D030421:Peroxynitrous Acid; D019344:Lactic Acid; D014443:Tyrosine; D019289:Pyruvic Acid; D000449:Aldehyde Reductase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005978:Glutathione; D005947:Glucose