title: Tumor necrosis factor-α and lymphotoxin-α mediate myocardial ischemic injury via TNF receptor 1, but are cardioprotective when activating TNF receptor 2.
abstract: OBJECTIVE
  This study determines the roles of tumor necrosis factor-α (TNFα) and lymphotoxin-α (LTα) in post-myocardial infarction (post-MI) cardiac injury, and identifies the TNF receptor type responsible for TNFα- and LTα-mediated cardiac injury.
  
  
  RESULTS
  Adult male wild type (WT), TNFα(-/-), LTα(-/-), 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 TNFα and LTα levels in plasma, but in distinct temporal manner. Plasma TNFα peaked 1 day after MI, and decreased toward baseline 3 days after MI. In contrast, plasma LTα became significantly increased 3 days post-MI, and remained elevated thereafter. TNFα deletion significantly improved cardiac function 3 days, but not 7 days, after MI. In contrast, LTα 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).
  
  
  CONCLUSIONS
  Our study demonstrates that TNFα and LTα overproduction contribute to early and late cardiac dysfunction after MI, respectively. We provide clear evidence that both TNFα and LTα mediate post-MI cardiac dysfunction via TNFR1 stimulation, whereas TNFR2 activation is cardioprotective against ischemic injury. Simultaneous inhibition of TNFα and LTα or specific TNFR1 function blockade may represent superior cardioprotective approaches over general TNF activity suppression.
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianli
authors.initials: J
authors.lastname: Zhao
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Jiao
authors.forename: Baojiang
authors.initials: B
authors.lastname: Liu
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000097:blood / Q000378:metabolism*; D017353:Gene Deletion; D008233:Lymphotoxin-alpha / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D013318:Stroke Volume; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D002316:Cardiotonic Agents; D008233:Lymphotoxin-alpha; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha