Polyol pathway impairs the function of SERCA and RyR in ischemic-reperfused rat hearts by increasing oxidative modifications of these proteins.
A number of studies have shown that the polyol pathway, consisting of aldose reductase (AR) and sorbitol dehydrogenase (SDH), contributes to ischemia-reperfusion (I/R)-induced myocardial infarction due to depletion of ATP. In this report we show that the polyol pathway in I/R heart also contributes to the impairment of sacro/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and ryanodine receptor (RyR), two key players in Ca(2+) signaling that regulate cardiac contraction. Rat hearts were isolated and retrogradely perfused with either Krebs' buffer containing 1 microM AR inhibitor, zopolrestat, or 200 nM SDH inhibitor, CP-170,711, and challenged by 30 min of regional ischemia and 45 min of reperfusion. We found that post-ischemic contractile function of the isolated perfused hearts was improved by pharmacological inhibition of the polyol pathway. I/R-induced contractile dysfunction is most likely due to impairment in Ca(2+) signaling and the activities of SERCA and RyR. All these abnormalities were significantly ameliorated by treatment with ARI or SDI. We showed that the polyol pathway activities increase the level of peroxynitrite, which enhances the tyrosine nitration of SERCA and irreversibly modifies it to form SERCAC674-SO(3)H. This leads to reduced level of S-glutathiolated SERCA, contributing to its inactivation. The polyol pathway activities also deplete the level of GSH, leading to decreased active RyR, the S-glutathiolated RyR. Thus, in I/R heart, inhibition of polyol pathway improved the function of SERCA and RyR by protecting them from irreversible oxidation.
Tang
Wai Ho
WH
Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Kravtsov
Gennadi M
GM
Sauert
Martina
M
Tong
Xiao Yong
XY
Hou
Xiu Yun
XY
Wong
Tak Ming
TM
Chung
Sookja K
SK
Man Chung
Stephen Sum
SS
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D006321:Heart / Q000503:physiopathology*; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology; D015425:Myocardial Reperfusion; D010084:Oxidation-Reduction; D010793:Phthalazines; D011108:Polymers; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D052160:Benzothiazoles; D010793:Phthalazines; D011108:Polymers; D011506:Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C024617:polyol; C067172:zopolrestat; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase