TNF-α inhibitor protects against myocardial ischemia/reperfusion injury via Notchl-mediated suppression of oxidative/nitrative stress

TNF-alpha inhibitor reportedly protects against myocardial ischemia/reperfusion (MYR) injury. It can also increase Notch1 expression in inflammatory bowel disease, revealing the regulation of Notchl signaling by TNF-alpha inhibitor. However, the interaction between TNF-alpha inhibitor and Notchl signaling in MI/R remains unclear. This study aimed to determine the involvement of TNF-alpha inhibitor with Notchl in MI/R and delineate the related mechanism. Notchl -specific small interfering RNA (20 mu g) or Jaggedl (a Notch ligand, 12 mu g) 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 24 h (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 Notchl 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, Notchl blockade increased the expression of inducible NO synthase (iNOS) and gp(91phox), 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 Notchl downregulation in mice treated with etanercept. Additionally, either Notch] activation with Jaggedl 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-alpha inhibitor, partly via Notchl signaling-mediated suppression of oxidative/nitrative stress. (C) 2015 Elsevier Inc. All rights reserved.