Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo

Straßburger, Maria; Bloch, Wilhelm; Sulyok, Silke; Schüller, Jutta; Keist, Alexander F.; Schmidt, Annette; Wenk, Jutta; Peters, Thorsten; Wlaschek, Meinhard; Krieg, Thomas; Hafner, Martin; Kümin, Angelika; Werner, Sabine; Müller, Werner; Scharffetter‐­Kochanek, Karin

doi:10.1016/j.freeradbiomed.2005.02.009

Cited by 111 publications

(112 citation statements)

References 65 publications

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“…In contrast to mice with heterozygous Sod2 deficiency in all organs (Van Remmen et al, 2003;Strassburger et al, 2005), we found a complex premature aging phenotype with skin atrophy, osteoporosis, muscle degeneration and a significantly reduced lifespan in the mutant mice. Fibroblasts in the skin of mutant mice revealed an increase in the expression of p16 INK4a , but did not undergo enhanced apoptosis, suggesting that atrophy in the skin, and most likely also in other organs, is due to the instalment of an oxidative damageinduced senescence programme.…”

Section: Introductioncontrasting

confidence: 80%

“…To circumvent early lethality of Sod2-deficient mice (Li et al, 1995;Lebovitz et al, 1996;Strassburger et al, 2005) and to address the impact of connective tissue-specific Sod2 deficiency on aging of individual organs and lifespan, we have used a connective tissue-specific strategy with the introduction of loxP sites flanking exon 3 of the Sod2 gene (Strassburger et al, 2005). Deletion of exon 3 completely abrogates Sod2 activity, as exon 3 codes for the Sod2 tetramer formation domain (Li et al, 1995).…”

Section: Generation Of the Mutant Phenotypementioning

confidence: 99%

“…Deletion of exon 3 completely abrogates Sod2 activity, as exon 3 codes for the Sod2 tetramer formation domain (Li et al, 1995). Mice carrying the floxed Sod2 allele (Sod2 f ⁄ f ) (Strassburger et al, 2005) were bred with Col1a2-Cre + Sod2 + ⁄ + transgenic mice (Florin et al, 2004) to generate Col1a2-Cre + Sod2 + ⁄ f mice. The connective tissue-specific Cre expression was achieved by the activation of a2(I) collagen promoter.…”

Section: Generation Of the Mutant Phenotypementioning

confidence: 99%

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Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

et al. 2010

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SummaryThe free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchymederived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissuespecific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16 INK4a , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissuespecific anti-aging strategies.

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Section: Introductioncontrasting

confidence: 80%

Section: Generation Of the Mutant Phenotypementioning

confidence: 99%

Section: Generation Of the Mutant Phenotypementioning

confidence: 99%

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Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

et al. 2010

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“…Such evidence has led to heightened interest in the clinical application of antioxidants for neurological disorders, including DN (Paolisso et al, 1994;Natarajan et al, 2002;Henriksen, 2006;Coverley and Baxter, 1997). One caveat is that the SOD2 +/− mice also display evidence of cardiovascular insufficiency (Ohashi et al, 2006;Strassburger et al, 2005). Reduced nerve blood flow also may contribute to DN through mechanisms that only partially involve oxidative stress (Ishii et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, SOD2 +/− mice also display decreased activity of aconitase and NADH oxidoreductase and increased levels of intra-mitochondrial protein carbonyls and damaged mitochondrial DNA (Williams et al, 1998). They also display evidence of decreased acetylcholine-induced arterial relaxation (Ohashi et al, 2006) and increased myocardial degeneration (Strassburger et al, 2005) that both lead to impaired blood flow.…”

Section: Introductionmentioning

confidence: 99%

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

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Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that over expression of SOD2 decreases superoxide (O 2 •− ) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Under expression of SOD2 in dissociated DRG cultures from adult SOD2 +/− mice results in increased levels of O 2 •− , activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2 +/− C57BL/6J mice and their SOD2 +/+ litter mates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.

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Large‐scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis

Aigner¹,

Fundel²,

Saas³

et al. 2006

Arthritis & Rheumatism

314

253

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Objective. Despite many research efforts in recent decades, the major pathogenetic mechanisms of osteoarthritis (OA), including gene alterations occurring during OA cartilage degeneration, are poorly understood, and there is no disease-modifying treatment approach. The present study was therefore initiated in order to identify differentially expressed disease-related genes and potential therapeutic targets.Methods. This investigation consisted of a large gene expression profiling study performed based on 78 normal and disease samples, using a custom-made complementary DNA array covering >4,000 genes.Results. Many differentially expressed genes were identified, including the expected up-regulation of anabolic and catabolic matrix genes. In particular, the down-regulation of important oxidative defense genes, i.e., the genes for superoxide dismutases 2 and 3 and glutathione peroxidase 3, was prominent. This indicates that continuous oxidative stress to the cells and the matrix is one major underlying pathogenetic mechanism in OA. Also, genes that are involved in the phenotypic stability of cells, a feature that is greatly reduced in OA cartilage, appeared to be suppressed.Conclusion. Our findings provide a reference data set on gene alterations in OA cartilage and, importantly, indicate major mechanisms underlying central cell biologic alterations that occur during the OA disease process. These results identify molecular targets that can be further investigated in the search for therapeutic interventions.

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Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo

Cited by 111 publications

References 65 publications

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Large‐scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis

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