title: Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo.
abstract: To circumvent the early lethality of manganese superoxide dismutase (SOD2)-deficient mice, we have used a skin-specific strategy with introduction of loxP sites flanking exon 3 of the SOD2 gene. To our surprise, when breeding a female keratin 14 Cre transgenic mouse to a SOD2 "floxed" male mouse, due to keratin 14 promoter-driven Cre expression in the oocytes, all offspring were heterozygous for SOD2. In sharp contrast to initial publications on SOD2(+/-) mice, the herein reported mice on a mixed genetic background (C57BL/6 x 129/Ola) in their heterozygous state (SOD(+/-)) revealed distinct ultrastructural damage of the myocard, with swelling and disruption of mitochondria and accumulation of lipid droplets, increased nitrotyrosine formation, and lipid peroxidation as well as activation of apoptosis signaling pathways in the heart in vivo. Strikingly, and so far unreported, we found a substantial decrease in the activity of the cytosolic copper, zinc superoxide dismutase (SOD1) in the heart tissue of SOD2(+/-) mice, suggesting that the breakdown of mitochondrial membranes in the heart of SOD2(+/-) mice results in the enhanced release of superoxide anion radicals or derivatives thereof with subsequent inactivation of cytosolic SOD1. This model may be particularly suited to long-term studies on age-related heart failure as well as other age-related diseases and the polygenic base of tissue-specific responses to oxidative injury.
authors.affiliation: Department of Dermatology and Allergology, University of Ulm, Maienweg 12, 89081 Ulm, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Strassburger
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Silke
authors.initials: S
authors.lastname: Sulyok
authors.forename: Jutta
authors.initials: J
authors.lastname: Schüller
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Keist
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Jutta
authors.initials: J
authors.lastname: Wenk
authors.forename: Thorsten
authors.initials: T
authors.lastname: Peters
authors.forename: Meinhard
authors.initials: M
authors.lastname: Wlaschek
authors.forename: Jacek
authors.initials: J
authors.lastname: Lenart
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Martin
authors.initials: M
authors.lastname: Hafner
authors.forename: Angelika
authors.initials: A
authors.lastname: Kümin
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005822:Genetic Vectors; D005979:Glutathione Peroxidase / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009865:Oocytes / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011995:Recombination, Genetic; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C002744:3-nitrotyrosine; D014443:Tyrosine; D012313:RNA; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C045073:Cre recombinase; D019426:Integrases; D012260:Ribonucleases; D010100:Oxygen