Tumor necrosis factor-α and tumor necrosis factor receptors in the failing human heart

Guillermo Torre, Samir Kapadia, Joseph Lee, Jean Bernard Durand, Roger D. Bies, James B. Young, Douglas L. Mann

Research output: Contribution to journalArticle

858 Scopus citations

Abstract

Background: Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that produces negative inotropic effects in the heart. Recently, elevated levels of TNF-α have been reported in patients with advanced congestive heart failure. Although TNF-α is thought to exert its deleterious effects by binding to two cell surface receptors, TNFR1 and TNFR2, the level of expression and regulation of TNF receptors in the heart in cardiac disease states is not known. Methods and Results: We examined mRNA and protein levels for TNFR1, TNFR2, and TNF-α in explanted hearts from organ donors as well as in patients with end-stage dilated cardiomyopathy (DCM) and ischemic heart disease (IHD). Northern blot analysis revealed that mRNA for TNFR1 and TNFR2 was present in nonfailing. DCM, and IHD hearts, TNFR1 and TNFR2 receptor protein levels, as measured by ELISA, were decreased 60% in DCM and IHD patients compared with nonfailing hearts (P<.005). To determine a potential mechanism for the decrease in TNF receptor expression, we measured levels of circulating soluble TNF receptors (sTNFRs) in DCM and IHD patients. This analysis showed that there was a significant one-and-a-half to threefold increase in sTNFRs in DCM (P<.03) and IHD patients (P<.001). Another important finding was that TNF-α mRNA and TNF-α protein were present in the explanted hearts from DCM and IHD patients but not in nonfailing hearts. Conclusions: In summary, the results of this study constitute the initial demonstration that TNF receptor proteins are dynamically regulated in patients with advanced congestive heart failure. Moreover, the observation that failing hearts express elevated levels of TNF-α suggests thai overexpression of this cytokine may be one of several different maladaptive mechanisms responsible for the progressive cardiac decompensation that occurs in advanced heart failure.

Original languageEnglish (US)
Pages (from-to)704-711
Number of pages8
JournalCirculation
Volume93
Issue number4
DOIs
StatePublished - Feb 15 1996

Keywords

  • cells
  • heart failure
  • receptors
  • tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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