title: Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis.
abstract: We show here that exposure of cardiac cells to simulated ischemia results in apoptosis and is accompanied by phosphorylation and increased expression and transcriptional activity of STAT-1. Similarly, interferon-gamma, which is known to induce STAT-1 activation, also induced apoptosis in cardiac cells. STAT-1-transfected cells were more susceptible to ischemia-induced cell death than cells transfected with a control plasmid lacking the STAT-1 coding sequence. Furthermore, an antisense STAT-1 vector reduced both ischemia- and overexpressed STAT-1-induced cell death in cardiac cells. Both STAT-1 overexpression and interferon-gamma treatment or exposure to ischemia activated the promoter of the pro-apoptotic caspase-1 gene in cardiomyocytes. Finally, ischemia/reperfusion also induced STAT-1 activation and caspase-1 processing in ventricular myocytes in the intact heart ex vivo. Immunofluorescent staining demonstrated an increase in STAT-1-positive staining in cardiomyocytes in response to ischemia/reperfusion that co-localized with terminal deoxynucleotidyl transferase dVTP nick end-labeling-positive apoptotic cells. These results suggest that STAT-1 plays a critical role in the regulation of ischemia/reperfusion-induced apoptosis in cardiac cells, acting at least in part via a caspase-1 activation-dependent pathway.
authors.affiliation: Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. Stephanov@yahoo.com
authors.forename: A
authors.initials: A
authors.lastname: Stephanou
authors.forename: B K
authors.initials: BK
authors.lastname: Brar
authors.forename: T M
authors.initials: TM
authors.lastname: Scarabelli
authors.forename: A K
authors.initials: AK
authors.lastname: Jonassen
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
authors.forename: M S
authors.initials: MS
authors.lastname: Marber
authors.forename: R A
authors.initials: RA
authors.lastname: Knight
authors.forename: D S
authors.initials: DS
authors.lastname: Latchman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006352:Heart Ventricles; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators