Basic Research in Cardiology

, Volume 106, Issue 6, pp 1193–1205

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

Authors

  • Jason B. Garlie
    • Institute of Molecular CardiologyUniversity of Louisville
    • Department of Physiology and BiophysicsUniversity of Louisville
  • Tariq Hamid
    • Institute of Molecular CardiologyUniversity of Louisville
  • Yan Gu
    • Institute of Molecular CardiologyUniversity of Louisville
  • Mohamed Ameen Ismahil
    • Institute of Molecular CardiologyUniversity of Louisville
  • Bysani Chandrasekar
    • Southeast Louisiana Veterans Health Care System, Tulane University School of Medicine
    • Institute of Molecular CardiologyUniversity of Louisville
    • Department of Physiology and BiophysicsUniversity of Louisville
    • Robley Rex VA Medical Center
    • Division of Cardiovascular MedicineUniversity of Louisville
Original Contribution

DOI: 10.1007/s00395-011-0196-6

Cite this article as:
Garlie, J.B., Hamid, T., Gu, Y. et al. Basic Res Cardiol (2011) 106: 1193. doi:10.1007/s00395-011-0196-6

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.

Keywords

Tumor necrosis factorBeta-adrenergic receptorCardiac hypertrophyCytokinesNuclear factor kappa B

Supplementary material

395_2011_196_MOESM1_ESM.pdf (320 kb)
Supplementary material 1 (PDF 320 kb)

Copyright information

© Springer-Verlag 2011