title: Disruption of Nox2 and TNFRp55/p75 eliminates cardioprotection induced by anisomycin.
abstract: Transient activation of p38 through anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75(-/-) and Nox2(-/-) mice received intraperitoneal injections of anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2(-/-) mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to anisomycin-induced cardioprotection.
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, China.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Jun T
authors.initials: JT
authors.lastname: Liu
authors.forename: Tai L
authors.initials: TL
authors.lastname: Guo
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D000841:Anisomycin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases