Document Detail

Importance of FADD signaling in serum deprivation- and hypoxia-induced cardiomyocyte apoptosis.
MedLine Citation:
PMID:  12063258     Owner:  NLM     Status:  MEDLINE    
Although cardiomyocyte (CM) apoptosis has been well described in both in vitro and in vivo models of ischemic heart disease, the intracellular pathways leading to CM death have not been fully characterized. To define the role of death receptor signaling in CM apoptosis, we constructed recombinant adenoviral vectors carrying wild-type (wt) or dominant negative (dn) forms of the death receptor adaptor protein FADD (Fas-associated death domain protein) and used these vectors to transduce rat neonatal CMs in models of hypoxia- and serum deprivation (SD)-induced apoptosis. The combination of SD and hypoxia induced rapid activation of caspase-3 and -8 as well as DNA fragmentation, reaching a plateau within 4-8 h. Adenoviral expression of FADD-dn inhibited caspase-8 activation as well as hypoxia/SD-induced apoptosis at 24 h in an moi (multiplicity of infection)-dependent manner. In contrast, adenoviral expression of FADD-wt increased apoptosis and caspase-3 activity in CMs under both normoxic and hypoxic conditions. Surprisingly, FADD-dn, as well as the specific caspase-8 inhibitor benzyloxycarbonyl-IETD-fluoromethylketone also inhibited the activation of caspase-9 and -3 in CMs subjected to hypoxia/SD. These data suggest a primary role for FADD/caspase-8 signaling that is necessary and sufficient for apoptosis of CMs subjected to hypoxia/SD.
Wei Chao; Yan Shen; Ling Li; Anthony Rosenzweig
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2002-06-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-08-30     Completed Date:  2002-10-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  31639-45     Citation Subset:  IM    
Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
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MeSH Terms
Adaptor Proteins, Signal Transducing*
Amino Acid Chloromethyl Ketones / pharmacology
Animals, Newborn
Apoptosis / physiology*
Carrier Proteins / physiology*
Caspase 3
Caspase 8
Caspase 9
Caspases / antagonists & inhibitors,  metabolism
Cell Hypoxia / physiology*
Cells, Cultured
Culture Media, Serum-Free
Cysteine Proteinase Inhibitors / pharmacology
Fas-Associated Death Domain Protein
Heart / physiology*
Myocardium / cytology*,  enzymology
Signal Transduction / physiology*
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Amino Acid Chloromethyl Ketones; 0/Carrier Proteins; 0/Culture Media, Serum-Free; 0/Cysteine Proteinase Inhibitors; 0/Fadd protein, rat; 0/Fas-Associated Death Domain Protein; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Casp8 protein, rat; EC 3.4.22.-/Casp9 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases

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