title: TNF-α inhibitor protects against myocardial ischemia/reperfusion injury via Notch1-mediated suppression of oxidative/nitrative stress.
abstract: TNF-α inhibitor reportedly protects against myocardial ischemia/reperfusion (MI/R) injury. It can also increase Notch1 expression in inflammatory bowel disease, revealing the regulation of Notch1 signaling by TNF-α inhibitor. However, the interaction between TNF-α inhibitor and Notch1 signaling in MI/R remains unclear. This study aimed to determine the involvement of TNF-α inhibitor with Notch1 in MI/R and delineate the related mechanism. Notch1-specific small interfering RNA (20 μg) or Jagged1 (a Notch ligand, 12 μg) was delivered through intramyocardial injection. Forty-eight hours after injection, mice received 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress) or 24h (for infarct size and cardiac function) of reperfusion. Ten minutes before reperfusion, mice randomly received an intraperitoneal injection of vehicle, etanercept, diphenyleneiodonium, 1400W, or EUK134. Finally, downregulation of Notch1 significantly reversed the alleviation of MI/R injury induced by etanercept, as evidenced by enlarged myocardial infarct size, suppressed cardiac function, and increased myocardial apoptosis. Moreover, Notch1 blockade increased the expression of inducible NO synthase (iNOS) and gp(91)(phox), enhanced NO and superoxide production, and accelerated their cytotoxic reaction product, peroxynitrite. Furthermore, NADPH inhibition with diphenyleneiodonium or iNOS suppression with 1400W mitigated the aggravation of MI/R injury induced by Notch1 downregulation in mice treated with etanercept. Additionally, either Notch1 activation with Jagged1 or peroxynitrite decomposition with EUK134 reduced nitrotyrosine content and attenuated MI/R injury. These data indicate that MI/R injury can be attenuated by TNF-α inhibitor, partly via Notch1 signaling-mediated suppression of oxidative/nitrative stress.
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Haifeng
authors: H
authors: Pei
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Xiaofeng
authors: X
authors: Song
authors: Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang 110016, China.
authors: Chengfei
authors: C
authors: Peng
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Yan
authors: Y
authors: Tan
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Ying
authors: Y
authors: Li
authors: Department of Anatomy, Histology, and Embryology and K.K. Leung Brain Research Center, Fourth Military Medical University, Xi׳an 710032, China.
authors: Xia
authors: X
authors: Li
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Shuangtao
authors: S
authors: Ma
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Qiang
authors: Q
authors: Wang
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Rong
authors: R
authors: Huang
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: Dachun
authors: D
authors: Yang
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors: De
authors: D
authors: Li
authors: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors: Erhe
authors: E
authors: Gao
authors: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China. Electronic address: yyj10001@126.com.
authors: Yongjian
authors: Y
authors: Yang
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D000068800:Etanercept; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009249:NADP / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009861:Onium Compounds / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology; D000072099:Serrate-Jagged Proteins; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D002135:Calcium-Binding Proteins; C433928:EUK-134; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D009861:Onium Compounds; D009942:Organometallic Compounds; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D012459:Salicylates; D000072099:Serrate-Jagged Proteins; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D009249:NADP; C007517:diphenyleneiodonium; D052247:Nitric Oxide Synthase Type II; D000068800:Etanercept
keywords: Free radicals; Myocardial ischemia/reperfusion; Notch1; Oxidative/nitrative stress; TNF-α inhibitor