Deferoxamine induces prolonged cardiac preconditioning via accumulation of oxygen radicals.
Iron chelation by deferoxamine (DFO) blocks the Fenton reaction, but also inhibits prolyl hydroxylases and thereby activates certain hypoxia-inducible transcription factors (HIFs) that trigger cellular adaptation to hypoxia. Because both mechanisms may alleviate tissue damage in ischemia and reperfusion, we tried to differentiate their contribution to DFO-induced cardioprotection. Myocardial ischemia and reperfusion were induced in anesthetized Wistar rats. Infarct size was related to the ischemic area. Myocardial mRNA expression was determined by real-time PCR. Radical reactivity was probed in myocardial tissue slices with the redox-sensitive dye CM-H(2)DCFDA. Single ip applications of DFO (200 mg/kg) administered 2 h to 3 days before infarction reduced infarct size from 55 +/- 7% to 22-26%. Protection was abolished by the radical scavenger N-(2-mercaptopropionyl)glycine and the protein kinase C inhibitor chelerythrine when either was given 30 min before DFO, whereas subsequent application was ineffective. DFO did not alter the expression of various HIF target genes, whereas mRNAs of HIF-independent genes, aldose reductase and glucose transporter-4, were increased in infarcted myocardium 2 days after DFO treatment. Enhancement of superoxide activity by DFO could be demonstrated in vitro. Acute and prolonged myocardial preconditioning is triggered by DFO in response to accumulation of oxygen radicals and activation of protein kinase C.
Dendorfer
Andreas
A
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany. dendorfe@medinf.mu-luebeck.de
Heidbreder
Marc
M
Hellwig-Bürgel
Thomas
T
Jöhren
Olaf
O
Qadri
Fatimunnisa
F
Dominiak
Peter
P
D000449:Aldehyde Reductase / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D053119:Benzophenanthridines; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology*; D051275:Glucose Transporter Type 4; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D000449:Aldehyde Reductase; D000470:Alkaloids; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D053119:Benzophenanthridines; D004268:DNA-Binding Proteins; D003676:Deferoxamine; D051275:Glucose Transporter Type 4; D005998:Glycine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010617:Phenanthridines; D011493:Protein Kinase C; D018336:Receptors, Aryl Hydrocarbon; D013438:Sulfhydryl Compounds; D013481:Superoxides; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497398:ARNT protein, rat; C424683:Hif3a protein, rat; C110658:N-(2-mercaptoproprionyl)-glycine; C495694:Slc2a4 protein, rat; C016299:chelerythrine