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.
- Late preconditioning
- Myocardial infarction
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine