The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury
The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury
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糖尿病心肌缺血再灌注损伤期间 RAGE 与硝基硫氧还蛋白失活之间的替代串扰
DOI：
10.1152/ajpendo.00075.2012
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发表时间：
2012-10-01
影响因子：
5.1
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Liu, Yi;Qu, Yan;Tao, Ling
Liu Y，Qu Y，Wang R，Ma Y，Xia C，Gao C，Liu J，Lian K，Xu A，Lu X，Sun L，Yang L，Lau WB，Gao E，Koch W，Wang H，Tao L.糖尿病心肌缺血-再灌注损伤中硫氧还蛋白失活与硝化失活的交替串扰。Am J Physiol Endocrinol Metab 303：E841-E852，2012.首次发表于2012年7月24日; doi：10.1152/ajpendo.00075.2012.-糖基化终末产物受体（receptor for advanced glycation end products，RECEPTOR）和硫氧还蛋白（thioredoxin，Trx）在糖尿病心肌缺血再灌注损伤中起着相反的作用。我们最近证明了Trx的硝化修饰导致其失活和心脏保护作用的丧失。本研究旨在确定糖尿病心脏MI/R损伤加重时，β-淀粉样蛋白表达增强和Trx活性降低之间的关系。通过多次腹腔注射低剂量链脲佐菌素诱导小鼠糖尿病状态。分别于MI/R前经心肌内和腹腔内注射小干扰RNA（siRNA）和可溶性干扰RNA（ssiRNA）。使小鼠经受30分钟的心肌梗死，随后再灌注3或24小时。在再灌注前10分钟，糖尿病小鼠随机接受EUK 134（过氧亚硝酸盐清除剂），重组hTrx-1，硝化Trx-1，夹竹桃素（NADPH氧化酶抑制剂），或1400 W [诱导型一氧化氮合酶（iNOS）抑制剂]给药。糖尿病心脏表现出MI/R后的TRx-1表达和N-e-（羧甲基）赖氨酸（CML，主要晚期糖基化终产物亚型）含量增加，Trx-1活性降低，Trx硝化增加。在糖尿病小鼠中，siRNA或给予sodium可降低MI/R诱导的iNOS和gp 91（phox）表达，减少Trx硝化，保留Trx活性，并减少梗死面积。Apocynin或1400 W显著降低硝基酪氨酸的产生并恢复Trx活性。相反，给予EUK 134或减少的hTrx，但不硝化hTrx，衰减MI/R诱导的超氧化物产生，表达和CML含量，并减少糖尿病小鼠心肌细胞凋亡。总的来说，我们证明，TRX硝化失活方式的MI/R损伤的调制。相反地，Trx的硝化修饰阻断了其对糖尿病心脏中β 1受体表达的抑制作用。这是第一个直接的证据表明，替代串扰之间的过表达和硝化Trx失活，这表明干预干预其相互作用可能是减轻糖尿病MI/R损伤的新手段。
Liu Y, Qu Y, Wang R, Ma Y, Xia C, Gao C, Liu J, Lian K, Xu A, Lu X, Sun L, Yang L, Lau WB, Gao E, Koch W, Wang H, Tao L. The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 303: E841-E852, 2012. First published July 24, 2012; doi:10.1152/ajpendo.00075.2012.-The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardioprotection. The present study is to determine the relationship between augmented RAGE expression and diminished Trx activity pertaining to exacerbated MI/R injury in the diabetic heart. The diabetic state was induced in mice by multiple intraperitoneal low-dose streptozotocin injections. RAGE small-interfering RNA (siRNA) or soluble RAGE (sRAGE, a RAGE decoy) was via intramyocardial and intraperitoneal injection before MI/R, respectively. Mice were subjected to 30 min of myocardial infarction followed by 3 or 24 h of reperfusion. At 10 min before reperfusion, diabetic mice were randomized to receive EUK134 (peroxynitrite scavenger), recombinant hTrx-1, nitrated Trx-1, apocynin (a NADPH oxidase inhibitor), or 1400W [an inducible nitric oxide synthase (iNOS) inhibitor] administration. The diabetic heart manifested increased RAGE expression and N-e-(carboxymethyl) lysine (CML, major advanced glycation end product subtype) content, reduced Trx-1 activity, and increased Trx nitration after MI/R. RAGE siRNA or administration of sRAGE in diabetic mice decreased MI/R-induced iNOS and gp91(phox) expression, reduced Trx nitration, preserved Trx activity, and decreased infarct size. Apocynin or 1400W significantly decreased nitrotyrosine production and restored Trx activity. Conversely, administration of either EUK134 or reduced hTrx, but not nitrated hTrx, attenuated MI/R-induced superoxide production, RAGE expression, and CML content and decreased cardiomyocyte apoptosis in diabetic mice. Collectively, we demonstrate that RAGE modulates the MI/R injury in a Trx nitrative inactivation fashion. Conversely, nitrative modification of Trx blocked its inhibitory effect upon RAGE expression in the diabetic heart. This is the first direct evidence demonstrating the alternative cross talk between RAGE overexpression and nitrative Trx inactivation, suggesting that interventions interfering with their interaction may be novel means of mitigating diabetic MI/R injury.