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This Article Full Text Full Text (PDF) All Versions of this Article: 289/5/H2073    most recent 01216.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Chao, W. Articles by Rosenzweig, A. Search for Related Content PubMed PubMed Citation Articles by Chao, W. Articles by Rosenzweig, A.

Fas-associated death-domain protein inhibits TNF- mediated NF-B activation in cardiomyocytes

¹Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown; ²Department of Anesthesia and Critical Care, and ³Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and ⁴Department of Anesthesia, Medical College of Georgia, Augusta, Georgia

Submitted 6 December 2004 ; accepted in final form 3 June 2005

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-B signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-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- activated NF-B in CMs as demonstrated by phosphorylation and degradation of inhibitory-B (IB)--enhanced nuclear p65 and NF-B DNA-binding activity as well as increased mRNA for the NF-B-dependent adhesion molecule VCAM-1 (19 ± 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF--induced IB- phosphorylation, decreased p65 nuclear translocation and NF-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-B activation. The effects of FADD on NF-B were cell-type specific. FADD expression also inhibited TNF--mediated NF-B activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-B in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-B activation as well as phosphorylation of IB- and IB kinase (IKK)- in response to cytokine stimulation or expression of the upstream kinases NF-B-inducing kinase and IKK-. These data demonstrate that FADD inhibits NF-B activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-.

signal transduction; cardiac; inflammation; tumor necrosis factor; nuclear factor-B

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