Fas-associated death-domain protein inhibits TNF-α mediated NFκB activation in cardiomyocytes

被引:11
作者
Chao, W
Shen, Y
Li, L
Zhao, HL
Meiler, SE
Cook, SA
Rosenzweig, A
机构
[1] Massachusetts Gen Hosp, Program Cardiovasc Gene Therapy, Cardiovasc Res Ctr, Charlestown, MA USA
[2] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA USA
[3] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA
[4] Med Coll Georgia, Dept Anesthesia, Augusta, GA 30912 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2005年 / 289卷 / 05期
关键词
signal transduction; cardiac; inflammation; tumor necrosis factor; nuclear factor-kappa B;
D O I
10.1152/ajpheart.01216.2004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:H2073 / H2080
页数:8
相关论文
共 37 条
[1]   The Fas-associated death domain protein suppresses activation of NF-κB by LPS and IL-1β [J].
Bannerman, DD ;
Tupper, JC ;
Kelly, JD ;
Winn, RK ;
Harlan, JM .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (03) :419-425
[2]   Importance of FADD signaling in serum deprivation - and hypoxia-induced cardiomyocyte apoptosis [J].
Chao, W ;
Shen, Y ;
Li, L ;
Rosenzweig, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (35) :31639-31645
[3]   Activation of the NF-κB pathway by Caspase 8 and its homologs [J].
Chaudhary, PM ;
Eby, MT ;
Jasmin, A ;
Kumar, A ;
Liu, L ;
Hood, L .
ONCOGENE, 2000, 19 (39) :4451-4460
[4]   FADD, A NOVEL DEATH DOMAIN-CONTAINING PROTEIN, INTERACTS WITH THE DEATH DOMAIN OF FAS AND INITIATES APOPTOSIS [J].
CHINNAIYAN, AM ;
OROURKE, K ;
TEWARI, M ;
DIXIT, VM .
CELL, 1995, 81 (04) :505-512
[5]  
Chinnaiyan AM, 1996, J BIOL CHEM, V271, P4961
[6]   NF-κB:: pivotal mediator or innocent bystander in atherogenesis? [J].
Collins, T ;
Cybulsky, MI .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (03) :255-264
[7]   Transcriptional effects of chronic Akt activation in the heart [J].
Cook, SA ;
Matsui, T ;
Li, L ;
Rosenzweig, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (25) :22528-22533
[8]   A20 is dynamically regulated in the heart and inhibits the hypertrophic response [J].
Cook, SA ;
Novikov, MS ;
Ahn, Y ;
Matsui, T ;
Rosenzweig, A .
CIRCULATION, 2003, 108 (06) :664-667
[9]   A cytokine-responsive I kappa B kinase that activates the transcription factor NF-kappa B [J].
DiDonato, JA ;
Hayakawa, M ;
Rothwarf, DM ;
Zandi, E ;
Karin, M .
NATURE, 1997, 388 (6642) :548-554
[10]   Nuclear factor-κB regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells [J].
Erl, W ;
Hansson, GK ;
de Martin, R ;
Draude, G ;
Weber, KSC ;
Weber, C .
CIRCULATION RESEARCH, 1999, 84 (06) :668-677