Increased insulin, triglycerides, reactive oxygen species, and cardiac fibrosis in mice with a mutation in the helicase domain of the Werner syndrome gene homologue

Massip, Laurent; Garand, Chantal; Turaga, Ramachander V N; Deschênes, François; Thorin, Éric; Lebel, Michel

doi:10.1016/j.exger.2005.10.011

Cited by 66 publications

(67 citation statements)

References 48 publications

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“…A severe defenestration was observed in mutants from 7 mo onward (Fig. 2C, D), which coincides with the appearance of significant hyperlipidemia and the onset of diabetes in Wrn Δhel/Δhel animals (13). The overall porosity (determined as the percentage of the endothelial surface perforated by fenestrations) was very low in the Wrn Δhel/Δhel mice (0.91± 0.69%) compared to age-matched WT mice (4.1± 0.3%) (23).…”

Section: Resultsmentioning

confidence: 98%

“…Diabetes, hyperlipidemia, and enhanced visceral fat accretion were reported in patients with WS (33) and Wrn Δhel/Δhel mice (13). The unfolding of these phenotypes was monitored in ascorbate-treated and untreated Wrn Δhel/Δhel mice.…”

Section: Resultsmentioning

confidence: 99%

“…ROS and oxidative DNA damage measurements were performed as described previously (13). Briefly, liver tissues were excised, rinsed with PBS to remove blood, and homogenized with a Dremel tissue homogenizer (BioSpec Products, Bartlesville, OK) in 1 ml of RIPA buffer (50 mM Tris HCl, pH 7.5; 150 mM NaCl; 1% Nonidet P-40; 0.1% SDS; and 0.5% deoxycholate).…”

Section: Detection Of Ros and Oxidative Dna Damage In Tissuesmentioning

confidence: 99%

“…This dye is highly fluorescent on oxidation. The oxidized dye was measured as described previously (13). Protein concentrations were measured using the Bradford assay.…”

Section: Detection Of Ros and Oxidative Dna Damage In Tissuesmentioning

confidence: 99%

“…The remaining tissues were embedded in paraffin for histology. Oxidative DNA damage was measured as described previously (13).…”

Section: Detection Of Ros and Oxidative Dna Damage In Tissuesmentioning

confidence: 99%

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Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Detection Of Ros and Oxidative Dna Damage In Tissuesmentioning

confidence: 99%

“…This dye is highly fluorescent on oxidation. The oxidized dye was measured as described previously (13). Protein concentrations were measured using the Bradford assay.…”

Section: Detection Of Ros and Oxidative Dna Damage In Tissuesmentioning

confidence: 99%

“…The remaining tissues were embedded in paraffin for histology. Oxidative DNA damage was measured as described previously (13).…”

Section: Detection Of Ros and Oxidative Dna Damage In Tissuesmentioning

confidence: 99%

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