title: Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction.
abstract: Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. TNF-alpha initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-alpha has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-alpha expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1beta, transforming growth factor-beta, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1beta were significantly further upregulated in R2KO mice. TNF-alpha is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Monden
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Takaki
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kawano
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha