Tumor Necrosis Factor-α and Lymphotoxin-α Mediate Myocardial Ischemic Injury via TNF Receptor 1, but Are Cardioprotective When Activating TNF Receptor 2

Objective: This study determines the roles of tumor necrosis factor-alpha (TNF alpha) and lymphotoxin-alpha (LT alpha) in post-myocardial infarction (post-MI) cardiac injury, and identifies the TNF receptor type responsible for TNF alpha- and LT alpha-mediated cardiac injury. Methods and Results: Adult male wild type (WT), TNF alpha(-/-), LT alpha(-/-), TNFR1(-/-), and TNFR2(-/-) mice were subjected to MI via coronary artery occlusion. Functional, histological, and biochemical analyses were performed 1 to 7 days post-MI. In WT mice, MI significantly increased both TNF alpha and LT alpha levels in plasma, but in distinct temporal manner. Plasma TNF alpha peaked 1 day after MI, and decreased toward baseline 3 days after MI. In contrast, plasma LTa became significantly increased 3 days post-MI, and remained elevated thereafter. TNF alpha deletion significantly improved cardiac function 3 days, but not 7 days, after MI. In contrast, LT alpha deletion had no effect upon cardiac dysfunction 3 days after MI, but improved cardiac function 7 days after MI. More importantly, knockout of TNFR1 and TNFR2 had opposite effects upon post-MI cardiac dysfunction, which was markedly attenuated by TNFR1 deletion (P<0.01 vs. WT), but exacerbated by TNFR2 deletion (P<0.05 vs. WT). Conclusion: Our study demonstrates that TNF alpha and LT alpha overproduction contribute to early and late cardiac dysfunction after MI, respectively. We provide clear evidence that both TNF alpha and LT alpha mediate post-MI cardiac dysfunction via TNFR1 stimulation, whereas TNFR2 activation is cardioprotective against ischemic injury. Simultaneous inhibition of TNF alpha and LT alpha or specific TNFR1 function blockade may represent superior cardioprotective approaches over general TNF activity suppression.