The role of TNF-α receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning

Michael P. Flaherty, Yiru Guo, Sumit Tiwari, Arash Rezazadeh, Greg Hunt, Santosh K. Sanganalmath, Xian Liang Tang, Roberto Bolli, Buddhadeb Dawn

Research output: Contribution to journalArticlepeer-review

Abstract

The specific role of TNF-α 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-α 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-α (TNF-α-/-), 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-α-/- and p55-/-/p75-/- mice, but also in p55-/- and p75-/- mice, indicating that TNF-α signaling via both p55 and p75 is necessary for the development of protection. In nonpreconditioned TNF-α-/-, 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-α 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.

Original languageEnglish (US)
Pages (from-to)735-741
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume45
Issue number6
DOIs
StatePublished - Dec 1 2008

Keywords

  • Cytokine
  • Late preconditioning
  • Myocardial infarction
  • Receptor
  • TNF-α
  • p55
  • p75

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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