title: Cardioprotection against myocardial infarction with PTD-BIR3/RING, a XIAP mimicking protein.
abstract: The purpose of the present study was to investigate the potential cardioprotective effects of an original approach based on the properties of the X chromosome-linked Inhibitor of Apoptosis (XIAP), the most effective endogenous inhibitor of apoptosis. For this purpose, the C-terminal part of XIAP (BIR3 and RING domains) was fused to the protein transduction domain (PTD) of the HIV1 transactivator of transcription, which confers to fused protein the ability to cross cell membranes. This protein, so-called PTD-BIR3/RING, was administered intravenously in C57BL/6J mice subjected to 30 min coronary artery occlusion and 24 h of reperfusion. Administration of PTD-BIR3/RING at 5 min before and 30 min after the onset of reperfusion reduced infarct size vs control (23+/-2% vs 41+/-4% and 27+/-4% vs 41+/-3%, respectively, p<0.05). Similar reduction in infarct size was observed when PTD-BIR3/RING was administered prior to ischemia (28+/-1% vs 44+/-3%). In addition to inhibition of caspase-3 and -9 activities, PTD-BIR3/RING induced an inhibition of caspase-8 and several other actors of the apoptotic pathways. In conclusion, this study demonstrates that the administration of PTD-BIR3/RING reduces myocardial infarct size even when injected during reperfusion through interruption of caspase activation by pharmacologically mimicking endogenous XIAP.
authors.affiliation: Plateforme Petit Animal, INSERM U 955, Créteil, F-94010, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Souktani
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pons
authors.forename: Christelle
authors.initials: C
authors.lastname: Guegan
authors.forename: Omar
authors.initials: O
authors.lastname: Bouhidel
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Roland
authors.initials: R
authors.lastname: Zini
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.forename: Brigitte
authors.initials: B
authors.lastname: Onteniente
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D020169:Caspases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases