Model mice for tissue-specific deletion of the manganese superoxide dismutase gene.
Manganese superoxide dismutase (Mn-SOD) is a mitochondrial enzyme that converts toxic O(2)(-) to H(2)O(2). Previous studies have reported that a systemic deficiency in Mn-SOD causes neonatal lethality in mice. Therefore, no mouse model is available for the analysis of the pathological role of O(2)(-) injuries in adult tissues. To explore an adult-type mouse model, we generated tissue-specific Mn-SOD conditional knockout mice using a Cre-loxp system. First, we generated liver-specific Mn-SOD-deficient mice by crossbreeding with albumin-Cre transgenic mice. Mn-SOD proteins were significantly downregulated in the liver of liver-specific Mn-SOD knockout mice. Interestingly, the mutant mice showed no obvious morphological abnormalities or biochemical alterations in the liver, suggesting a redundant or less important physiological role for Mn-SOD in the liver than previously thought. Next, we generated heart/muscle-specific Mn-SOD-deficient mice by crossbreeding muscle creatine kinase-Cre transgenic mice. The mutant mice developed progressive dilated cardiomyopathy with specific molecular defects in mitochondrial respiration. Furthermore, brain-specific Mn-SOD-deficient mice that had been developed by crossbreeding with nestin-Cre transgenic mice developed a spongiform encephalopathy-like pathology associated with gliosis and died within 3 weeks of birth. These results imply that the superoxide generated in mitochondria plays a pivotal role in the development and progression of pathologies in the heart and brain, but not in the liver. In conclusion, we successfully generated various tissue-specific Mn-SOD conditional knockout mice that provide useful tools for the analysis of various oxidative stress-associated diseases.
Shimizu
Takahiko
T
Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology,Tokyo, Japan. shimizut@tmig.or.jp
Nojiri
Hidetoshi
H
Kawakami
Satoru
S
Uchiyama
Satoshi
S
Shirasawa
Takuji
T
D000375:Aging / Q000502:physiology; D000818:Animals; D001927:Brain Diseases / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology; D017353:Gene Deletion; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology; D015151:Immunoblotting; D008099:Liver / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009200:Myocardial Contraction / Q000502:physiology; D009928:Organ Specificity; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*
D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase