Basic Research in Cardiology

, Volume 106, Issue 6, pp 1193–1205 | Cite as

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

  • Jason B. Garlie
  • Tariq Hamid
  • Yan Gu
  • Mohamed Ameen Ismahil
  • Bysani Chandrasekar
  • Sumanth D. Prabhu
Original Contribution


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.


Tumor necrosis factor Beta-adrenergic receptor Cardiac hypertrophy Cytokines Nuclear factor kappa B 

Supplementary material

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


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jason B. Garlie
    • 1
    • 2
  • Tariq Hamid
    • 1
  • Yan Gu
    • 1
  • Mohamed Ameen Ismahil
    • 1
  • Bysani Chandrasekar
    • 3
  • Sumanth D. Prabhu
    • 1
    • 2
    • 4
    • 5
  1. 1.Institute of Molecular CardiologyUniversity of LouisvilleLouisvilleUSA
  2. 2.Department of Physiology and BiophysicsUniversity of LouisvilleLouisvilleUSA
  3. 3.Southeast Louisiana Veterans Health Care System, Tulane University School of MedicineNew OrleansUSA
  4. 4.Robley Rex VA Medical CenterLouisvilleUSA
  5. 5.Division of Cardiovascular MedicineUniversity of LouisvilleLouisvilleUSA

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