Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 33, Issue 7, Pages 988-997Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0891-5849(02)00989-9
Keywords
oxygen radicals; ROS; apoptosis; SOD mimetics; metalloporphyrins; heme oxygenase; free radicals
Funding
- NCI NIH HHS [CA 77822] Funding Source: Medline
- NCRR NIH HHS [RR 01008] Funding Source: Medline
- NHLBI NIH HHS [1P01 HL 68769-01] Funding Source: Medline
- NINDS NIH HHS [NS 40494] Funding Source: Medline
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The cytoprotective effects of redox-active metalloporphyrins (e.g., FeTBAP and MnTBAP) were generally attributed to their ability to scavenge reactive oxygen and nitrogen species. In this study, we evaluated the pro- and antiapoptotic potentials of different metalloporphyrins containing iron, cobalt, zinc, and manganese in adult rat cardiomyocytes exposed to doxorubicin (DOX), an anticancer drug that forms superoxide and hydrogen peroxide via redox-cycling of DOX semiquinone in the presence of molecular oxygen. We used electron spin resonance/spin trapping and cytochrome c reduction to assess the scavenging of superoxide anion by metalloporphyrins. Superoxide anion was effectively scavenged by FeTBAP and MnTBAP but not by CoTBAP and ZnTBAP. FeTBAP efficiently scavenged H2O2. Both CoTBAP and FeTBAP inhibited DOX-induced cardiomyocyte apoptosis. These findings implicate that mechanisms other than oxy-radical scavenging may account for their antiapoptotic property. In addition, CoTBAP and FeTBAP induced heme oxygenase-1 more potently than did MnTBAP and ZnTBAP. Inhibition of heme oxygenase abolished the protective effect of CoTBAP and reduced the protection by FeTBAP against DOX-induced cardiomyocyte apoptosis. We propose that metalloporphyrins can inhibit apoptosis either by inducing heme oxygenase-1 and antiapoptotic protein signaling or by scavenging reactive oxygen species. (C) 2002 Elsevier Science Inc.
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