title: The metalloporphyrin FeTPPS but not by cyclosporin A antagonizes the interaction of peroxynitrate and hydrogen peroxide on cardiomyocyte cell death.
abstract: The objective of this study was to determine whether the metalloporphyrin, 5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron (III) chloride (FeTPPS), antagonized the effect of peroxynitrite, oxygen-free radicals, and the combination of the two, on cardiomyocyte cell viability. We further sought to compare the effects of FeTPPS to an inhibitor of the mitochondrial transmembrane permeability transition pores (PTP)-cyclosporin A. Cardiomyocytes from embryonic chick heart were treated with 3-morpholinosydnonimine (SIN-1), which decomposes to liberate NO and superoxide anion (O(2) (-)) which in turn generates peroxynitrite. FeTPPS antagonized cell death induced by either SIN-1 or H(2)O(2). The combination of H(2)O(2) plus SIN-1 further enhanced the amount of cell death over SIN-1 alone. FeTPPS rescued cells from almost complete cell death with the combination of SIN-1 plus H(2)O(2). SIN-1 induced cardiac protein nitration, including mitochondrial proteins as demonstrated by Western blotting with nitrotyrosine-specific antibodies. FeTPPS reduced cellular protein nitration. SIN-1-induced loss of mitochondrial transmembrane permeability transition pores potential was visualized with fluorescent dye staining and was reversed by FeTPPS. In contrast, the mitochondrial PTP blocker cyclosporin A did not alter SIN-1-induced cell death. In summary, these data demonstrate the enhanced cellular lethality of the combination of peroxynitrite and reactive oxygen species from hydrogen peroxide. A mitochondrial death pathway was implicated as nitration of mitochondrial proteins was induced by peroxynitrite that also induced a loss of DeltaPsim that was prevented by FeTPPS. In contrast, cyclosporin did not antagonize the effects of SIN-1. The ability of FeTPPS to reduce reactive nitrogen-induced cell death, and protein nitration suggests that FeTPPS is a useful agent to maintain cell viability and is better than cyclosporin in this situation.
authors.affiliation: University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
authors.forename: Shaun S
authors.initials: SS
authors.lastname: Klassen
authors.forename: Simon W
authors.initials: SW
authors.lastname: Rabkin
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002385:linsidomine; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D008981:Molsidomine
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