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Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2005 Jun 01; Vol. 38 (11), pp. 1458-70. - Publication Year :
- 2005
-
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.
- Subjects :
- Animals
Blotting, Western
Electrophoresis, Polyacrylamide Gel
Embryo, Mammalian cytology
Female
Genetic Vectors
Glutathione Peroxidase metabolism
Immunohistochemistry
Integrases metabolism
Lipid Peroxidation
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Genetic
Myocardium metabolism
Oocytes metabolism
Oxidative Stress
Oxygen metabolism
Phenotype
Promoter Regions, Genetic
RNA metabolism
RNA, Messenger metabolism
Recombination, Genetic
Ribonucleases metabolism
Signal Transduction
Stem Cells cytology
Superoxide Dismutase metabolism
Tyrosine analogs & derivatives
Tyrosine chemistry
Tyrosine metabolism
Apoptosis
Heterozygote
Myocardium pathology
Superoxide Dismutase genetics
Superoxide Dismutase physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0891-5849
- Volume :
- 38
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 15890620
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2005.02.009