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1.
PLoS Genet ; 10(10): e1004686, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25299392

RESUMO

As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.


Assuntos
Envelhecimento , Proteínas de Ligação a DNA/deficiência , Deficiências Nutricionais/etiologia , Endonucleases/deficiência , Proteínas Nucleares/deficiência , Fatores de Transcrição/deficiência , Envelhecimento/genética , Animais , Encéfalo/patologia , Caquexia/etiologia , Caquexia/genética , Sistema Nervoso Central/fisiologia , Sistema Nervoso Central/fisiopatologia , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Deficiências Nutricionais/genética , Modelos Animais de Doenças , Endonucleases/genética , Endonucleases/metabolismo , Feminino , Fígado/patologia , Longevidade/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteoporose/etiologia , Osteoporose/genética , Gravidez , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
EuroIntervention ; 4(1): 139-47, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-19112791

RESUMO

AIMS: To study how the balance between tacrolimus elution and polymer degradation from drug-eluting stents (DES) affects neointimal thickening (NIT) in swine coronary arteries. METHODS AND RESULTS: We assessed a fast-degrading high dose (2 microg/mm2), a slow degrading low dose (1 microg/mm2) or polymer-only coated DES (Pol) versus bare metal stent (BMS). Coronary segments were pre-injured with a balloon/artery ratio of 1.1 to 1.3. Then stents were implanted at that site with a stent/artery ratio of 1.1, with a follow-up period of 5 to 180 days. Histology showed a well endothelialised neointima (82 +/- 1% in high dose DES vs. 93 +/- 8% in BMS) already at five days, without differences in eNOS expression. Morphometry indicated that neointimal thickness in DES was significantly reduced as compared to BMS and Pol at 28 and 90 days. Polymer degradation products induced a distinct inflammatory response which was effectively suppressed in DES. Between 90 and 180 days, however, the slow degrading low-dose stent showed catch-up of NIT. CONCLUSIONS: Tacrolimus eluted from a biodegradable stent coating can suppress the inflammatory effect of the coating degradation products if the balance between the drug levels and the degradation products is favorable.


Assuntos
Angioplastia Coronária com Balão , Stents Farmacológicos , Imunossupressores/farmacologia , Ácido Láctico , Ácido Poliglicólico , Tacrolimo/farmacologia , Vasculite/patologia , Animais , Materiais Revestidos Biocompatíveis , Vasos Coronários/lesões , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Stents Farmacológicos/efeitos adversos , Elastina/metabolismo , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Imuno-Histoquímica , Metais , Óxido Nítrico Sintase Tipo III/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Sus scrofa , Suínos , Porco Miniatura , Túnica Íntima/lesões , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Média/lesões , Túnica Média/metabolismo , Túnica Média/patologia , Vasculite/etiologia
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