Divergent tumor necrosis factor receptor-related remodeling responses in heart failure:Role of nuclear factor-κB and inflammatory activation

Academic Article

Abstract

  • Although preclinical data suggested that tumor necrosis factor-α (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. 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)-κB, p38 mitogen-activated protein kinase, and JNK2 and upregulation of TNF, interleukin (IL)-1|β, 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-kB, 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-κB and p38 mitogen-activated protein kinase activation, higher IL-113 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-kB activation was proapoptotic, an effect dependent on TNFR1 signaling, whereas TNFR2 overexpression attenuated TNF-induced NF-κB activation. TNFR1 and TNFR2 have disparate and opposing effects on remodeling, hypertrophy, NF-kB, 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. © 2009 American Heart Association, Inc.
  • Published In

  • Circulation  Journal
  • Digital Object Identifier (doi)

    Author List

  • Hamid T; Gu Y; Ortines RV; Bhattacharya C; Wang G; Xuan YT; Prabhu SD
  • Start Page

  • 1386
  • End Page

  • 1397
  • Volume

  • 119
  • Issue

  • 10