title: Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation.
abstract: BACKGROUND
  Although preclinical data suggested that tumor necrosis factor-alpha (TNF) neutralization in heart failure (HF) would be beneficial, clinical trials of TNF antagonists were paradoxically negative. We hypothesized that TNF induces opposing inflammatory and remodeling responses in HF that are TNF-receptor (TNFR) specific.
  
  
  RESULTS
  HF was induced in wild-type (WT), TNFR1(-/-), and TNFR2(-/-) mice via coronary ligation. Compared with WT HF, 4-week postinfarction survival was significantly improved in both TNFR1(-/-) and TNFR2(-/-) HF. Compared with sham, WT HF hearts exhibited significant remodeling with robust activation of nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase, and JNK2 and upregulation of TNF, interleukin (IL)-1beta, IL-6, and IL-10. Compared with WT HF, TNFR1(-/-) HF exhibited (1) improved remodeling, hypertrophy, and contractile function; (2) less apoptosis; and (3) diminished NF-kappaB, p38 mitogen-activated protein kinase, and JNK2 activation and cytokine expression. In contrast, TNFR2(-/-) HF showed exaggerated remodeling and hypertrophy, increased border zone fibrosis, augmented NF-kappaB and p38 mitogen-activated protein kinase activation, higher IL-1beta and IL-6 gene expression, greater activated macrophages, and greater apoptosis. Oxidative stress and diastolic function were improved in both TNFR1(-/-)and TNFR2(-/-) HF. In H9c2 cardiomyocytes, sustained NF-kappaB activation was proapoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-kappaB activation.
  
  
  CONCLUSIONS
  TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-kappaB, inflammation, and apoptosis in HF: TNFR1 exacerbates, whereas TNFR2 ameliorates, these events. However, signaling through both receptors is required to induce diastolic dysfunction and oxidative stress. TNFR-specific effects in HF should be considered when therapeutic anti-TNF strategies are developed.
authors.affiliation: Institute Institute of Molecular Cardiology, Department of Medicine, University of Louisville and Louisville Veterans Affairs Medical Center, Louisville, KY 40202, USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Hamid
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Roger V
authors.initials: RV
authors.lastname: Ortines
authors.forename: Chhandashri
authors.initials: C
authors.lastname: Bhattacharya
authors.forename: Guangwu
authors.initials: G
authors.lastname: Wang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology; D002478:Cells, Cultured; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009200:Myocardial Contraction; D009205:Myocarditis / Q000209:etiology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology*; D018384:Oxidative Stress; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007378:Interleukins; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048056:Mitogen-Activated Protein Kinase 9; D048051:p38 Mitogen-Activated Protein Kinases