The metalloporphyrin FeTPPS but not by cyclosporin A antagonizes the interaction of peroxynitrate and hydrogen peroxide on cardiomyocyte cell death.
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.
Klassen
Shaun S
SS
University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
Rabkin
Simon W
SW
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
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
Curr Vasc Pharmacol. 2005 Jul;3(3):215-20
16026318
J Neurochem. 2001 Oct;79(2):445-55
11677273
Free Radic Biol Med. 2003 Feb 15;34(4):397-408
12566065
Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8641-5
8078937
Crit Care Med. 1997 May;25(5):812-9
9187601
Biochim Biophys Acta. 2000 May 6;1485(1):45-55
10802248
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11584-9
9751709
J Clin Invest. 2005 Mar;115(3):500-8
15765131
Arch Biochem Biophys. 1991 Aug 1;288(2):481-7
1654835
Cardiovasc Res. 2003 Oct 15;60(1):108-18
14522412
Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):444-8
1346070
Free Radic Biol Med. 1997;23(2):331-8
9199896
Biochem J. 1976 Feb 15;154(2):295-305
180973
Amino Acids. 2007;32(4):501-15
17077966
In Vivo. 2004 May-Jun;18(3):293-309
15341185
J Biol Chem. 1998 Jun 19;273(25):15646-53
9624158
Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3089-100
11087267
Mol Cell Biochem. 2005 Oct;278(1-2):39-51
16180087
Am J Physiol. 1995 May;268(5 Pt 1):L699-722
7762673
Int Arch Allergy Immunol. 2005 Jun;137(2):104-14
15855792
J Biol Chem. 2005 Feb 18;280(7):5983-93
15574409
Nitric Oxide. 2004 Feb;10(1):11-9
15050530
Circulation. 1989 Nov;80(5):1115-27
2553296
Cardiovasc Res. 2005 Aug 1;67(2):225-33
16005301
Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H39-46
12933349
Cell Physiol Biochem. 2007;20(1-4):1-22
17595511
Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H371-81
15345482
Biochem J. 1994 Oct 1;303 ( Pt 1):295-301
7945255
Circulation. 2005 Mar 1;111(8):988-95
15710754
J Biol Chem. 2003 Sep 5;278(36):33972-7
12821649
Arch Biochem Biophys. 2003 Apr 15;412(2):196-206
12667483
Am J Physiol Lung Cell Mol Physiol. 2004 Aug;287(2):L262-8
15246980
Arch Biochem Biophys. 2001 Mar 15;387(2):307-17
11370855
J Cereb Blood Flow Metab. 2007 Aug;27(8):1453-62
17293848
Neurochem Res. 2004 Mar;29(3):579-87
15038605
Pharmacol Rev. 2002 Dec;54(4):619-34
12429871
Arch Biochem Biophys. 2004 Jan 1;421(1):99-107
14678790
Hypertension. 1994 Jun;23(6 Pt 2):1121-31
7515853
Eur Heart J. 1998 Feb;19 Suppl B:B2-11
9519346
Biochem J. 2004 Mar 15;378(Pt 3):959-66
14627438
Eur J Pharmacol. 1998 Apr 3;346(1):97-102
9617758
Eur J Pharmacol. 2008 May 31;586(1-3):1-8
18395709
J Biol Chem. 2003 Sep 26;278(39):37223-30
12857734
Biochim Biophys Acta. 1996 Jul 18;1275(1-2):5-9
8688451
Free Radic Biol Med. 2006 Sep 15;41(6):886-95
16934671
J Biol Chem. 1983 Dec 25;258(24):15346-54
6654916
J Biol Chem. 1988 Apr 15;263(11):5224-9
2833500
Am J Physiol. 1994 Oct;267(4 Pt 2):H1461-6
7943392
Mol Med. 2002 Oct;8(10):571-80
12477967
J Cardiovasc Pharmacol. 1989;14 Suppl 11:S13-22
2484692
Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
15688001
Free Radic Biol Med. 1998 Sep;25(4-5):385-91
9741577
Arch Biochem Biophys. 1999 Jan 15;361(2):331-9
9882464
Biol Chem. 1999 Jul-Aug;380(7-8):1025-8
10494856
Biochim Biophys Acta. 2004 Jul 23;1658(1-2):44-9
15282173
Free Radic Biol Med. 2003 Dec 1;35(11):1457-68
14642394
Biochem Cell Biol. 1994 Jul-Aug;72(7-8):289-96
7893468
Circ Res. 2004 Nov 12;95(10):957-70
15539639
J Nephrol. 2005 Jul-Aug;18(4):453-7
16245254
Mol Cell Biochem. 2004 Mar;258(1-2):1-13
15030165
Free Radic Biol Med. 2007 Feb 1;42(3):394-403
17210452
Circ Res. 2000 Aug 4;87(3):241-7
10926876
J Am Coll Cardiol. 2004 Jun 16;43(12):2348-58
15193704
Circulation. 2006 Sep 26;114(13):1395-402
16966583
Am J Respir Crit Care Med. 1999 Jul;160(1):1-9
10390372
J Biol Chem. 2002 Apr 26;277(17):15021-7
11839754
Biochem Biophys Res Commun. 1997 Jan 3;230(1):115-9
9020024
Physiol Rev. 2007 Jan;87(1):315-424
17237348
Luminescence. 1999 Nov-Dec;14(6):283-90
10602296
Clin Exp Pharmacol Physiol. 2007 Sep;34(9):933-7
17645643
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12056-61
11593016
Cardiovasc Res. 2003 Jun 1;58(3):663-70
12798440
Free Radic Biol Med. 2007 Aug 15;43(4):590-9
17640569
Carcinogenesis. 2002 Jun;23(6):929-41
12082014
Free Radic Biol Med. 2007 Oct 1;43(7):995-1022
17761297
IUBMB Life. 2000 Oct-Nov;50(4-5):245-50
11327317
Cardiovasc Res. 1999 Oct;44(1):47-59
10615389