title: The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury.
abstract: 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(ε)-(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.
authors: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi’an, China.
authors: Yi
authors: Y
authors: Liu
authors: Yan
authors: Y
authors: Qu
authors: Rutao
authors: R
authors: Wang
authors: Yanzhuo
authors: Y
authors: Ma
authors: Chenhai
authors: C
authors: Xia
authors: Chao
authors: C
authors: Gao
authors: Jingyi
authors: J
authors: Liu
authors: Kun
authors: K
authors: Lian
authors: Aibing
authors: A
authors: Xu
authors: Xiaoyan
authors: X
authors: Lu
authors: Lu
authors: L
authors: Sun
authors: Lu
authors: L
authors: Yang
authors: Wayne B
authors: WB
authors: Lau
authors: Erhe
authors: E
authors: Gao
authors: Walter
authors: W
authors: Koch
authors: Haichang
authors: H
authors: Wang
authors: Ling
authors: L
authors: Tao
mesh_terms: D000098:Acetophenones / Q000627:therapeutic use; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009942:Organometallic Compounds / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012459:Salicylates / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D000098:Acetophenones; C433928:EUK-134; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007097:Imines; D008562:Membrane Glycoproteins; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D009942:Organometallic Compounds; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012459:Salicylates; C515559:Txn1 protein, mouse; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D013879:Thioredoxins; C048496:N(6)-carboxymethyllysine; C056165:acetovanillone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D008239:Lysine