Polyol pathway impairs the function of SERCA and RyR in ischemic-reperfused rat hearts by increasing oxidative modifications of these proteins

被引:41
作者
Tang, Wai Ho [1 ]
Kravtsov, Gennadi M. [1 ]
Sauert, Martina [1 ]
Tong, Xiao Yong [3 ]
Hou, Xiu Yun [3 ]
Wong, Tak Ming [1 ]
Chung, Sookja K. [2 ]
Chung, Stephen Sum Man [1 ]
机构
[1] Univ Hong Kong, Fac Med, Dept Physiol, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Fac Med, Dept Anat, Hong Kong, Hong Kong, Peoples R China
[3] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Vasc Biol Unit, Boston, MA 02118 USA
关键词
Polyol pathway; Aldose reductase; Sorbitol dehydrogenase; Calcium handling activity; Sacro/endoplasmic reticulum Ca2+-ATPase; Ryanodine receptor; S-glutathiolation; Tyrosine nitration; Oxidative stress; Myocardial Ischemia and reperfusion; SARCOPLASMIC-RETICULUM CA2+-ATPASE; ALDOSE REDUCTASE INHIBITION; S-GLUTATHIONYLATION; SMOOTH-MUSCLE; NITRIC-OXIDE; VENTRICULAR MYOCYTES; TYROSINE NITRATION; FREE-RADICALS; CA2+ RELEASE; INJURY;
D O I
10.1016/j.yjmcc.2009.12.003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 Ca2+-ATPase (SERCA) and ryanodine receptor (RyR), two key players in Ca2+ signaling that regulate cardiac contraction Rat hearts were Isolated and retrogradely perfused with either Krebs' buffer containing 1 mu M AR inhibitor, zopolrestat, or 200 nM SDH inhibitor, CP-170,711, and challenged by 30 min of regional ischemia and 45 mm 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 Ca2+ 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-SO3H 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 (C) 2009 Elsevier Ltd All rights reserved
引用
收藏
页码:58 / 69
页数:12
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