Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 289, Issue 5, Pages H2073-H2080Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01216.2004
Keywords
signal transduction; cardiac; inflammation; tumor necrosis factor; nuclear factor-kappa B
Funding
- NHLBI NIH HHS [HL-59521, HL-04336] Funding Source: Medline
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Fas-associated death-domain protein ( FADD) is an adaptor molecule that links death receptors to caspase-8 in many cell types including cardiomyocytes (CMs). Although FADD has previously been reported to play an important role in CM apoptosis, the effect of FADD on CM NF-kappa B signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-kappa B activation, we utilized adenoviral gene transfer of wild-type FADD and a truncation mutant that lacks the death-effector domain (FADD-DED) in rat CMs in vitro. TNF-alpha activated NF-kappa B in CMs as demonstrated by phosphorylation and degradation of inhibitory-kappa B (I kappa B)-alpha-enhanced nuclear p65 and NF-kappa B DNA-binding activity as well as increased mRNA for the NF-kappa B-dependent adhesion molecule VCAM-1 ( 19 +/- 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF-alpha-induced I kappa B-alpha phosphorylation, decreased p65 nuclear translocation and NF-kappa B DNA-binding activity, and reduced VCAM-1 transcript levels by 53-65%. Interestingly, FADD-DED exhibited a similar but weaker inhibitory effect on NF-kappa B activation. The effects of FADD on NF-kappa B were cell-type specific. FADD expression also inhibited TNF-alpha-mediated NF-kappa B activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-kappa B in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-kappa B activation as well as phosphorylation of I kappa B and I kappa B kinase (IKK)-beta in response to cytokine stimulation or expression of the upstream kinases NF-kappa B-inducing kinase and IKK-beta. These data demonstrate that FADD inhibits NF-kappa B activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-beta.
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