| First Author | Zhang Y | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 5 | Pages | e60227 |
| PubMed ID | 23704873 | Mgi Jnum | J:200841 |
| Mgi Id | MGI:5509408 | Doi | 10.1371/journal.pone.0060227 |
| Citation | Zhang Y, et al. (2013) Tumor necrosis factor-alpha and lymphotoxin-alpha mediate myocardial ischemic injury via TNF receptor 1, but are cardioprotective when activating TNF receptor 2. PLoS One 8(5):e60227 |
| abstractText | OBJECTIVE: This study determines the roles of tumor necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LTalpha) in post-myocardial infarction (post-MI) cardiac injury, and identifies the TNF receptor type responsible for TNFalpha- and LTalpha-mediated cardiac injury. METHODS AND RESULTS: Adult male wild type (WT), TNFalpha(-/-), LTalpha(-/-), 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 TNFalpha and LTalpha levels in plasma, but in distinct temporal manner. Plasma TNFalpha peaked 1 day after MI, and decreased toward baseline 3 days after MI. In contrast, plasma LTalpha became significantly increased 3 days post-MI, and remained elevated thereafter. TNFalpha deletion significantly improved cardiac function 3 days, but not 7 days, after MI. In contrast, LTalpha 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 TNFalpha and LTalpha overproduction contribute to early and late cardiac dysfunction after MI, respectively. We provide clear evidence that both TNFalpha and LTalpha mediate post-MI cardiac dysfunction via TNFR1 stimulation, whereas TNFR2 activation is cardioprotective against ischemic injury. Simultaneous inhibition of TNFalpha and LTalpha or specific TNFR1 function blockade may represent superior cardioprotective approaches over general TNF activity suppression. |
