title: Cellular redox status determines sensitivity to BNIP3-mediated cell death in cardiac myocytes.
abstract: The atypical BH3-only protein Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is an important regulator of hypoxia-mediated cell death. Interestingly, the susceptibility to BNIP3-mediated cell death differs between cells. In this study we examined whether there are mechanistic differences in BNIP3-mediated cell death between neonatal and adult cardiac myocytes. We discovered that BNIP3 is a potent inducer of cell death in neonatal myocytes, whereas adult myocytes are remarkably resistant to BNIP3. When exploring the potential underlying basis for the resistance, we discovered that adult myocytes express significantly higher levels of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD) than neonatal myocytes. Overexpression of MnSOD confers resistance to BNIP3-mediated cell death in neonatal myocytes. In contrast, the presence of a pharmacological MnSOD inhibitor, 2-methoxyestradiol, results in increased sensitivity to BNIP3-mediated cell death in adult myocytes. Cotreatment with the mitochondria-targeted antioxidant MitoTEMPO or the MnSOD mimetic manganese (III) tetrakis (4-benzoic acid) porphyrin chloride abrogates the increased cell death by 2-methoxyestradiol. Moreover, increased oxidative stress also restores the ability of BNIP3 to induce cell death in adult myocytes. Taken together, these data indicate that redox status determines cell susceptibility to BNIP3-mediated cell death. These findings are clinically relevant, given that pediatric hearts are known to be more vulnerable than the adult heart to ischemic injury. Our studies provide important insight into why pediatric hearts are more sensitive to ischemic injury and may help in the clinical management of childhood heart disease.
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California; and.
authors: Youngil
authors: Y
authors: Lee
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California; and.
authors: Dieter A
authors: DA
authors: Kubli
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California; and.
authors: Rita A
authors: RA
authors: Hanna
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California; and.
authors: Melissa Q
authors: MQ
authors: Cortez
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California; and.
authors: Hwa-Youn
authors: HY
authors: Lee
authors: Department of Pharmacology, University of California, San Diego, La Jolla, California.
authors: Shigeki
authors: S
authors: Miyamoto
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California; and Department of Pharmacology, University of California, San Diego, La Jolla, California asag@ucsd.edu.
authors: Åsa B
authors: ÅB
authors: Gustafsson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000975:Antioxidants; C505650:BNIP3 protein, rat; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D013482:Superoxide Dismutase
keywords: BNIP3; apoptosis; autophagy; cardiac myocytes; mitochondria; oxidative stress