Abstract 1000: Dichotomous Roles Of TNF-α Receptors p55 And p75 In Acute Ischemia/reperfusion Injury And Late Ischemic Preconditioning
We have previously demonstrated that TNF-alpha signaling is critical for the development of protection afforded by the late phase of ischemic preconditioning (PC). In the current study, we investigated the roles of p55 (TNFR-I) and p75 (TNFR-II) in acute myocardial ischemia/reperfusion injury as well as late PC. Wild-type (WT, B6 and B6,129 strains), TNF-a−/−, p55−/−, p75−/−, and p55−/−/p75−/− double-knockout mice underwent a 30-min coronary occlusion followed by 4 h of reperfusion with or without six cycles of coronary occlusion/reperfusion (O/R) 24 h earlier. Six cycles of O/R reduced infarct size 24 h later in B6 as well as B6,129 WT mice, indicating a rob ust late PC effect (Figure⇓). This infarct-sparing effect of late PC was abolished in the absence of TNF-a, p55, p75, and both p55/p75, indicating
that TNF-a signaling is critical for the development of late PC protection; and
that signaling via both p55 and p75 is necessary for the development of protection.
In nonpreconditioned TNF-a−/− and p75−/− mice, infarct size was similar to that observed in strain-matched WT mice (Figure⇓). However, infarct size in nonpreconditioned p55−/− mice was reduced compared with nonpreconditioned WT mice (46.8 ± 2.8% vs. 63.4 ± 3.2%, P < 0.05, Figure⇓). These observations were confirmed via linear regression analysis of myocardial risk region and infarct size. We conclude that nonredundant TNF-a signaling via both p55 and p75 is crucial for the development of late PC protection. However, the reduction in infarct size in naïve p55−/− mice indicates a deleterious role of this receptor during acute myocardial ischemia/reperfusion injury.