Tumor necrosis factor receptor 2 signaling limits β-adrenergic receptor-mediated cardiac hypertrophy in vivo.

Academic Article

Abstract

  • The in vivo role of TNF signaling in the genesis of β-adrenergic receptor (β-AR)-mediated cardiac hypertrophy is unknown. Wild-type (WT), TNF receptor 1 (TNFR1)-/- and TNFR2-/- mice were given isoproterenol (ISO, 12.5 μg/kg/h) or saline (SAL) for 1 or 7 days. In WT mice, 7 days of ISO yielded chamber/myocyte hypertrophy and hyperdynamic function without hypertension or fibrosis. WT ISO hearts exhibited an early (1 day) pro-inflammatory response with significant (p < 0.05) activation of nuclear factor (NF)-κB and activator protein 1 (AP-1) and upregulation of TNF, interleukin (IL)-1β and IL-6, inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein-1 (MCP-1), together with increased anti-inflammatory IL-10. This response diminished markedly by 7 days. As compared with WT ISO mice, TNFR1-/- ISO mice exhibited significantly (p < 0.05) less NF-κB and AP-1 activation, less IL-1β, TNF, iNOS and MCP-1 upregulation, but greater IL-10 at 1 day. However, there were no differences in hypertrophy or contractility at 7 days. In contrast, TNFR2-/- ISO mice exhibited augmented NF-κB and AP-1 activation, increased IL-1β and diminished IL-10 expression at 1 day, and significant exaggeration of hypertrophy and less contractile augmentation at 7 days. Moreover, TNFR2-/- mice exposed to tenfold higher ISO doses displayed significant mortality. TNF signaling contributes to β-AR-mediated cardiac remodeling in vivo in a receptor-specific manner. Unopposed TNFR1 activation is pro-inflammatory, pro-hypertrophic and promotes functional decline. However, co-activation of TNFR2 during β-AR stress is anti-inflammatory and counterbalances these deleterious effects. TNF modulatory strategies that maintain TNFR2 signaling may help prevent the detrimental long-term effects of β-AR stimulation in the heart.
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    Keywords

  • Adrenergic beta-Agonists, Animals, Blotting, Western, Cardiomegaly, Echocardiography, Enzyme-Linked Immunosorbent Assay, Isoproterenol, Male, Mice, Mice, Knockout, RNA, Messenger, Receptors, Adrenergic, beta, Receptors, Tumor Necrosis Factor, Type II, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction
  • Digital Object Identifier (doi)

    Author List

  • Garlie JB; Hamid T; Gu Y; Ismahil MA; Chandrasekar B; Prabhu SD
  • Start Page

  • 1193
  • End Page

  • 1205
  • Volume

  • 106
  • Issue

  • 6