title: The role of TNF-alpha receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning.
abstract: The specific role of TNF-alpha receptors I (TNFR-I, p55) and II (TNFR-II, p75) in myocardial ischemic injury remains unclear. Using genetically engineered mice, we examined the relative effects of TNF-alpha signaling via p55 and p75 in acute myocardial ischemia/reperfusion injury under basal conditions and in late preconditioning (PC). Wild-type (WT) (C57BL/6 and B6,129) mice and mice lacking TNF-alpha (TNF-alpha(-/-)), p55 (p55(-/-)), p75 (p75(-/-)), or both receptors (p55(-/-)/p75(-/-)) underwent 30 min of coronary occlusion and 24 h of reperfusion with or without six cycles of 4-min coronary occlusion/4-min reperfusion (O/R) 24 h earlier (ischemic PC). Six cycles of O/R reduced infarct size 24 h later in WT mice, indicating a late PC effect. This late PC-induced infarct-sparing effect was abolished not only in TNF-alpha(-/-) and p55(-/-)/p75(-/-) mice, but also in p55(-/-) and p75(-/-) mice, indicating that TNF-alpha signaling via both p55 and p75 is necessary for the development of protection. In nonpreconditioned TNF-alpha(-/-), p55(-/-)/p75(-/-), and p75(-/-) mice, infarct size was similar to strain-matched WT mice. In contrast, infarct size in nonpreconditioned p55(-/-) mice was reduced compared with nonpreconditioned WT mice. We conclude that (i) unopposed p75 signaling (in the absence of p55) reduces infarct size following acute ischemia/reperfusion injury in naive myocardium, whereas unopposed p55 signaling (in the absence of p75) has no effect; and (ii) the development of the infarct-sparing effects of the late phase of PC requires nonredundant signaling via both p55 and p75 receptors. These findings reveal a fundamental, heretofore unrecognized, difference between the two TNF-alpha receptors in the setting of myocardial ischemia/reperfusion injury: that is, both p55 and p75 are necessary for the development of protection during late PC, but only signaling via p75 is protective in nonpreconditioned myocardium.
authors.affiliation: Division of Cardiovascular Medicine and the Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Flaherty
authors.forename: Yiru
authors.initials: Y
authors.lastname: Guo
authors.forename: Sumit
authors.initials: S
authors.lastname: Tiwari
authors.forename: Arash
authors.initials: A
authors.lastname: Rezazadeh
authors.forename: Greg
authors.initials: G
authors.lastname: Hunt
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sanganalmath
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
mesh_terms: D000208:Acute Disease; D000818:Animals; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse