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[PMID]:28468757
[Au] Autor:Franken R; Teixido-Tura G; Brion M; Forteza A; Rodriguez-Palomares J; Gutierrez L; Garcia Dorado D; Pals G; Mulder BJ; Evangelista A
[Ad] Endereço:Servei de Cardiologia, Unitat de Marfan, Hospital Universitari, Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
[Ti] Título:Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome.
[So] Source:Heart;103(22):1795-1799, 2017 11.
[Is] ISSN:1468-201X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The effect of mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results. OBJECTIVES: This study aims to determine the impact of the mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality). METHODS: MFS patients with a pathogenic mutation followed at two specialised units were included. mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients. RESULTS: Two hundred and ninety patients with MFS were included: 113 (39%) with an HI- mutation and 177 (61%) with a DN- . At baseline, patients with HI- had a larger aortic root diameter than patients with DN- (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI- (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI- tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN- (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060). CONCLUSIONS: Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.
[Mh] Termos MeSH primário: Aneurisma Dissecante/genética
Aorta/patologia
Aneurisma Aórtico/genética
Fibrilina-1/genética
Síndrome de Marfan/genética
Mutação
[Mh] Termos MeSH secundário: Adolescente
Adulto
Aneurisma Dissecante/diagnóstico por imagem
Aneurisma Dissecante/metabolismo
Aorta/diagnóstico por imagem
Aneurisma Aórtico/diagnóstico por imagem
Aneurisma Aórtico/mortalidade
Análise Mutacional de DNA
Dilatação Patológica
Progressão da Doença
Ecocardiografia
Feminino
Predisposição Genética para Doença
Haploinsuficiência
Seres Humanos
Masculino
Síndrome de Marfan/complicações
Síndrome de Marfan/diagnóstico
Síndrome de Marfan/mortalidade
Meia-Idade
Fenótipo
Valor Preditivo dos Testes
Prognóstico
Estudos Retrospectivos
Fatores de Risco
Índice de Gravidade de Doença
Espanha
Fatores de Tempo
Adulto Jovem
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (FBN1 protein, human); 0 (Fibrillin-1)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1136/heartjnl-2016-310631


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[PMID]:28829846
[Au] Autor:Park HL; Kim JH; Jung Y; Park CK
[Ad] Endereço:Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea.
[Ti] Título:Racial Differences in the Extracellular Matrix and Histone Acetylation of the Lamina Cribrosa and Peripapillary Sclera.
[So] Source:Invest Ophthalmol Vis Sci;58(10):4143-4154, 2017 Aug 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: We investigated the extracellular matrix (ECM) of the lamina cribrosa (LC) and peripapillary sclera (PPS) and compared histone acetylation and related enzymes to identify racial differences between Korean and Caucasian donor eyes. Methods: Posterior segment tissues were obtained from 30 Caucasian donors and 42 age and axial length-matched Korean donors. Histone modification was assessed for histone deacetylase (HDAC) 2, HDAC3, and acetylated histone H3. The promoter regions of the major ECM in the LC and PPS including collagen type I and III, and elastic fiber components (elastin and fibrillin-1) and lysyl oxidase enzymes including lysyl oxidase-like 1 and 2 (LOXL2) were evaluated by chromatin immunoprecipitation (ChIP) assay. Protein and mRNA expression of major ECM components were assessed using real-time polymerase chain reaction analysis, western blot analysis, and immunohistochemical staining. Results: HDAC2 and HDAC3 expression levels were decreased and acetylated histone H3 was increased in the LC and PPS of Korean eyes than Caucasian eyes. The promoter regions of LOXL2, elastin, and fribrillin-1 genes were highly acetylated in Korean LC. Expression of LOXL2 and elastic fiber components (elastin and fibrillin-1) were significantly increased in Korean LC and PPS than Caucasians according to the real-time polymerase chain reaction, western blot analyses, and quantification of elastic fiber staining. Conclusions: Histone acetylation status differed in the promoter regions of the elastic fiber components and LOXL2 in the LC and PPS according to race. Further study to reveal the association with these findings to the pathogenesis of glaucoma in Korean eyes is needed.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático
Grupo com Ancestrais do Continente Europeu
Matriz Extracelular/metabolismo
Histona Desacetilase 2/metabolismo
Histona Desacetilases/metabolismo
Disco Óptico/metabolismo
Esclera/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Adulto
Idoso
Aminoácido Oxirredutases/metabolismo
Western Blotting
Elastina/metabolismo
Feminino
Fibrilina-1/metabolismo
Seres Humanos
Masculino
Meia-Idade
Regiões Promotoras Genéticas/fisiologia
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fibrillin-1); 9007-58-3 (Elastin); EC 1.4.- (Amino Acid Oxidoreductases); EC 1.4.3.- (LOXL2 protein, human); EC 3.5.1.98 (Histone Deacetylase 2); EC 3.5.1.98 (Histone Deacetylases); EC 3.5.1.98 (histone deacetylase 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-21474


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[PMID]:28708846
[Au] Autor:Renard M; Muiño-Mosquera L; Manalo EC; Tufa S; Carlson EJ; Keene DR; De Backer J; Sakai LY
[Ad] Endereço:Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
[Ti] Título:Sex, pregnancy and aortic disease in Marfan syndrome.
[So] Source:PLoS One;12(7):e0181166, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown. OBJECTIVES: In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17ß-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts. RESULTS: Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17ß-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells. CONCLUSIONS: Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.
[Mh] Termos MeSH primário: Aorta/fisiologia
Doenças da Aorta/patologia
Síndrome de Marfan/patologia
[Mh] Termos MeSH secundário: Adulto
Animais
Aorta/diagnóstico por imagem
Aorta/patologia
Doenças da Aorta/complicações
Modelos Animais de Doenças
Estradiol/farmacologia
Estrogênios/análise
Feminino
Fibrilina-1/genética
Fibrilina-1/metabolismo
Seres Humanos
Masculino
Síndrome de Marfan/complicações
Camundongos
Camundongos Endogâmicos C57BL
Miócitos de Músculo Liso/citologia
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
Gravidez
Estudos Retrospectivos
Fatores Sexuais
Fator de Crescimento Transformador beta1/análise
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Estrogens); 0 (Fibrillin-1); 0 (Transforming Growth Factor beta1); 4TI98Z838E (Estradiol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181166


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[PMID]:28619995
[Au] Autor:Tojais NF; Cao A; Lai YJ; Wang L; Chen PI; Alcazar MAA; de Jesus Perez VA; Hopper RK; Rhodes CJ; Bill MA; Sakai LY; Rabinovitch M
[Ad] Endereço:From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shrin
[Ti] Título:Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-ß in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension.
[So] Source:Arterioscler Thromb Vasc Biol;37(8):1559-1569, 2017 Aug.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly. APPROACH AND RESULTS: Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-ß1 (TGFß1). Thus, we considered whether BMPs like TGFß1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFß1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFß1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFß1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFß1 but only minimally so in mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFß1. In heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension. CONCLUSIONS: Disrupting BMPR2 impairs TGFß1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.
[Mh] Termos MeSH primário: Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo
Tecido Elástico/metabolismo
Hipertensão Pulmonar Primária Familiar/metabolismo
Hipertensão Pulmonar/metabolismo
Artéria Pulmonar/efeitos dos fármacos
Fator de Crescimento Transformador beta/farmacologia
Remodelação Vascular
[Mh] Termos MeSH secundário: Animais
Proteína Morfogenética Óssea 4/farmacologia
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/deficiência
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/deficiência
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética
Estudos de Casos e Controles
Células Cultivadas
Modelos Animais de Doenças
Tecido Elástico/patologia
Tecido Elástico/fisiopatologia
Elastina/genética
Elastina/metabolismo
Hipertensão Pulmonar Primária Familiar/genética
Hipertensão Pulmonar Primária Familiar/patologia
Hipertensão Pulmonar Primária Familiar/fisiopatologia
Fibrilina-1/genética
Fibrilina-1/metabolismo
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Fibroblastos/patologia
Predisposição Genética para Doença
Seres Humanos
Hipertensão Pulmonar/genética
Hipertensão Pulmonar/patologia
Hipertensão Pulmonar/fisiopatologia
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Camundongos Knockout
Mutação
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
Miócitos de Músculo Liso/patologia
Fenótipo
Artéria Pulmonar/metabolismo
Artéria Pulmonar/patologia
Artéria Pulmonar/fisiopatologia
Interferência de RNA
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Morphogenetic Protein 4); 0 (FBN1 protein, human); 0 (Fbn1 protein, mouse); 0 (Fibrillin-1); 0 (Transforming Growth Factor beta); 9007-58-3 (Elastin); EC 2.7.11.30 (BMPR2 protein, human); EC 2.7.11.30 (Bmpr1a protein, mouse); EC 2.7.11.30 (Bmpr2 protein, mouse); EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type I); EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type II)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309696


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[PMID]:28539414
[Au] Autor:Roohi J; Kang B; Bernard D; Bedja D; Dietz HC; Brody LC
[Ad] Endereço:McKusick-Nathans Institute of Genetic Medicine and.
[Ti] Título:Moderately Elevated Homocysteine Does Not Contribute to Thoracic Aortic Aneurysm in Mice.
[So] Source:J Nutr;147(7):1290-1295, 2017 Jul.
[Is] ISSN:1541-6100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA. We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA. Murine fibrillin 1 gene ( ) MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk. Cobalamin-restricted mice exhibited significantly higher homocysteine ( < 0.0001) and methylmalonic acid ( < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet. mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.
[Mh] Termos MeSH primário: Aneurisma da Aorta Torácica/etiologia
Homocisteína/sangue
Hiper-Homocisteinemia/complicações
[Mh] Termos MeSH secundário: Animais
Aneurisma da Aorta Torácica/genética
Feminino
Fibrilina-1/genética
Fibrilina-1/metabolismo
Masculino
Síndrome de Marfan/genética
Camundongos
Camundongos Endogâmicos C57BL
Mutação
Vitamina B 12/administração & dosagem
Deficiência de Vitamina B 12/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fbn1 protein, mouse); 0 (Fibrillin-1); 0LVT1QZ0BA (Homocysteine); P6YC3EG204 (Vitamin B 12)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.3945/jn.117.251173


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[PMID]:28485217
[Au] Autor:Uehara E; Hokazono H; Hida M; Sasaki T; Yoshioka H; Matsuo N
[Ad] Endereço:a Sanwa Shurui Co., Ltd. , Usa , Japan.
[Ti] Título:GABA promotes elastin synthesis and elastin fiber formation in normal human dermal fibroblasts (HDFs).
[So] Source:Biosci Biotechnol Biochem;81(6):1198-1205, 2017 Jun.
[Is] ISSN:1347-6947
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The multiple physiological effects of γ-aminobutyric acid (GABA) as a functional food component have been recently reported. We previously reported that GABA upregulated the expression of type I collagen in human dermal fibroblasts (HDFs), and that oral administration of GABA significantly increased skin elasticity. However, details of the regulatory mechanism still remain unknown. In this study, we further examined the effects of GABA on elastin synthesis and elastin fiber formation in HDFs. Real-time PCR indicated that GABA significantly increased the expression of tropoelastin transcript in a dose-dependent manner. Additionally, the expression of fibrillin-1, fibrillin-2, and fibulin-5/DANCE, but not lysyl oxidase and latent transforming factor-ß-binding protein 4, were also significantly increased in HDFs. Finally, immunohistochemical analysis confirmed that treatment with GABA dramatically increased the formation of elastic fibers in HDFs. Taken together, our results showed that GABA improves skin elasticity in HDFs by upregulating elastin synthesis and elastin fiber formation.
[Mh] Termos MeSH primário: Tecido Elástico/efeitos dos fármacos
Elastina/genética
Fibroblastos/efeitos dos fármacos
Tropoelastina/agonistas
Ácido gama-Aminobutírico/farmacologia
[Mh] Termos MeSH secundário: Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Derme/citologia
Derme/efeitos dos fármacos
Derme/metabolismo
Tecido Elástico/metabolismo
Elastina/agonistas
Elastina/metabolismo
Proteínas da Matriz Extracelular/agonistas
Proteínas da Matriz Extracelular/genética
Proteínas da Matriz Extracelular/metabolismo
Fibrilina-1/agonistas
Fibrilina-1/genética
Fibrilina-1/metabolismo
Fibrilina-2/agonistas
Fibrilina-2/genética
Fibrilina-2/metabolismo
Fibroblastos/citologia
Fibroblastos/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Proteínas de Ligação a TGF-beta Latente/genética
Proteínas de Ligação a TGF-beta Latente/metabolismo
Proteína-Lisina 6-Oxidase/genética
Proteína-Lisina 6-Oxidase/metabolismo
Transdução de Sinais
Tropoelastina/genética
Tropoelastina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Extracellular Matrix Proteins); 0 (FBLN5 protein, human); 0 (FBN1 protein, human); 0 (Fibrillin-1); 0 (Fibrillin-2); 0 (LTBP1 protein, human); 0 (Latent TGF-beta Binding Proteins); 0 (Tropoelastin); 56-12-2 (gamma-Aminobutyric Acid); 9007-58-3 (Elastin); EC 1.4.3.13 (Protein-Lysine 6-Oxidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.1080/09168451.2017.1290518


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[PMID]:28395026
[Au] Autor:White TL; Lewis P; Hayes S; Fergusson J; Bell J; Farinha L; White NS; Pereira LV; Meek KM
[Ad] Endereço:Structural Biophysics Research Group, School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cardiff, United Kingdom.
[Ti] Título:The Structural Role of Elastic Fibers in the Cornea Investigated Using a Mouse Model for Marfan Syndrome.
[So] Source:Invest Ophthalmol Vis Sci;58(4):2106-2116, 2017 Apr 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The presence of fibrillin-rich elastic fibers in the cornea has been overlooked in recent years. The aim of the current study was to elucidate their functional role using a mouse model for Marfan syndrome, defective in fibrillin-1, the major structural component of the microfibril bundles that constitute most of the elastic fibers. Methods: Mouse corneas were obtained from animals with a heterozygous fibrillin-1 mutation (Fbn1+/-) and compared to wild type controls. Corneal thickness and radius of curvature were calculated using optical coherence tomography microscopy. Elastic microfibril bundles were quantified and visualized in three-dimensions using serial block face scanning electron microscopy. Transmission electron microscopy was used to analyze stromal ultrastructure and proteoglycan distribution. Center-to-center average interfibrillar spacing was determined using x-ray scattering. Results: Fbn1+/- corneas were significantly thinner than wild types and displayed a higher radius of curvature. In the Fbn1+/- corneas, elastic microfibril bundles were significantly reduced in density and disorganized compared to wild-type controls, in addition to containing a higher average center-to-center collagen interfibrillar spacing in the center of the cornea. No other differences were detected in stromal ultrastructure or proteoglycan distribution between the two groups. Proteoglycan side chains appeared to colocalize with the microfibril bundles. Conclusions: Elastic fibers have an important, multifunctional role in the cornea as highlighted by the differences observed between Fbn1+/- and wild type animals. We contend that the presence of normal quantities of structurally organized elastic fibers are required to maintain the correct geometry of the cornea, which is disrupted in Marfan syndrome.
[Mh] Termos MeSH primário: Córnea/ultraestrutura
Tecido Elástico/ultraestrutura
Síndrome de Marfan/diagnóstico
[Mh] Termos MeSH secundário: Animais
Córnea/metabolismo
DNA/genética
Análise Mutacional de DNA
Modelos Animais de Doenças
Fibrilina-1/genética
Fibrilina-1/metabolismo
Síndrome de Marfan/genética
Síndrome de Marfan/metabolismo
Camundongos
Camundongos Mutantes
Microfibrilas/ultraestrutura
Microscopia Eletrônica de Varredura
Microscopia Eletrônica de Transmissão
Mutação
Tomografia de Coerência Óptica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fbn1 protein, mouse); 0 (Fibrillin-1); 9007-49-2 (DNA)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21358


  8 / 925 MEDLINE  
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[PMID]:28069701
[Au] Autor:Hulin A; Moore V; James JM; Yutzey KE
[Ad] Endereço:Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, ML7020, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
[Ti] Título:Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.
[So] Source:Cardiovasc Res;113(1):40-51, 2017 Jan.
[Is] ISSN:1755-3245
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIMS: Myxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/ß-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/ß-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined. METHODS AND RESULTS: To investigate the role of Wnt/ß-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/ß-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/ß-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/ß-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/ß-catenin signalling in the development of MVD. CONCLUSIONS: Altogether, these data indicate that Axin2 limits Wnt/ß-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/ß-catenin signalling resulting from loss of Axin2 leads to progressive MVD.
[Mh] Termos MeSH primário: Insuficiência da Valva Aórtica/metabolismo
Valva Aórtica/metabolismo
Proteína Axina/deficiência
Matriz Extracelular/metabolismo
Cardiopatias Congênitas/metabolismo
Insuficiência da Valva Mitral/metabolismo
Valva Mitral/metabolismo
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Agrecanas/metabolismo
Animais
Valva Aórtica/anormalidades
Valva Aórtica/fisiopatologia
Insuficiência da Valva Aórtica/patologia
Insuficiência da Valva Aórtica/fisiopatologia
Proteína Axina/genética
Proteínas Morfogenéticas Ósseas/metabolismo
Proliferação Celular
Colágeno/metabolismo
Matriz Extracelular/patologia
Fibrilina-1/genética
Fibrilina-1/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Predisposição Genética para Doença
Cardiopatias Congênitas/genética
Cardiopatias Congênitas/patologia
Cardiopatias Congênitas/fisiopatologia
Síndrome de Marfan/genética
Síndrome de Marfan/metabolismo
Síndrome de Marfan/patologia
Camundongos Knockout
Valva Mitral/anormalidades
Valva Mitral/fisiopatologia
Insuficiência da Valva Mitral/genética
Insuficiência da Valva Mitral/patologia
Insuficiência da Valva Mitral/fisiopatologia
Morfogênese
Mutação
Fenótipo
Fatores de Transcrição SOX9/genética
Fatores de Transcrição SOX9/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); 0 (Axin Protein); 0 (Axin2 protein, mouse); 0 (Bone Morphogenetic Proteins); 0 (Fbn1 protein, mouse); 0 (Fibrillin-1); 0 (SOX9 Transcription Factor); 0 (Sox9 protein, mouse); 9007-34-5 (Collagen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE
[do] DOI:10.1093/cvr/cvw229


  9 / 925 MEDLINE  
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[PMID]:28067899
[Au] Autor:Oller J; Méndez-Barbero N; Ruiz EJ; Villahoz S; Renard M; Canelas LI; Briones AM; Alberca R; Lozano-Vidal N; Hurlé MA; Milewicz D; Evangelista A; Salaices M; Nistal JF; Jiménez-Borreguero LJ; De Backer J; Campanero MR; Redondo JM
[Ad] Endereço:Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
[Ti] Título:Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome.
[So] Source:Nat Med;23(2):200-212, 2017 Feb.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.
[Mh] Termos MeSH primário: Proteína ADAMTS1/genética
Aneurisma Dissecante/genética
Aorta/metabolismo
Aneurisma Aórtico/genética
Síndrome de Marfan/genética
Óxido Nítrico Sintase Tipo II/genética
Óxido Nítrico/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS1/metabolismo
Adulto
Idoso
Aneurisma Dissecante/metabolismo
Animais
Aorta/efeitos dos fármacos
Aneurisma Aórtico/metabolismo
Aneurisma da Aorta Torácica/genética
Aneurisma da Aorta Torácica/metabolismo
Modelos Animais de Doenças
Inibidores Enzimáticos/farmacologia
Feminino
Fibrilina-1/genética
Técnicas de Silenciamento de Genes
Haploinsuficiência
Seres Humanos
Immunoblotting
Masculino
Síndrome de Marfan/metabolismo
Camundongos
Meia-Idade
NG-Nitroarginina Metil Éster/farmacologia
Óxido Nítrico Sintase Tipo II/antagonistas & inibidores
Óxido Nítrico Sintase Tipo II/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Fbn1 protein, mouse); 0 (Fibrillin-1); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (NOS2 protein, human); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 1.14.13.39 (Nos2 protein, mouse); EC 3.4.24.- (ADAMTS1 Protein); EC 3.4.24.- (ADAMTS1 protein, human); EC 3.4.24.- (Adamts1 protein, mouse); V55S2QJN2X (NG-Nitroarginine Methyl Ester)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170110
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4266


  10 / 925 MEDLINE  
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[PMID]:27956365
[Au] Autor:Brauchle E; Bauer H; Fernes P; Zuk A; Schenke-Layland K; Sengle G
[Ad] Endereço:Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Tuebingen, Germany; Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Stuttgart, Germany.
[Ti] Título:Raman microspectroscopy as a diagnostic tool for the non-invasive analysis of fibrillin-1 deficiency in the skin and in the in vitro skin models.
[So] Source:Acta Biomater;52:41-48, 2017 Apr 01.
[Is] ISSN:1878-7568
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Fibrillin microfibrils and elastic fibers are critical determinants of elastic tissues where they define as tissue-specific architectures vital mechanical properties such as pliability and elastic recoil. Fibrillin microfibrils also facilitate elastic fiber formation and support the association of epithelial cells with the interstitial matrix. Mutations in fibrillin-1 (FBN1) are causative for the Marfan syndrome, a congenital multisystem disorder characterized by progressive deterioration of the fibrillin microfibril/ elastic fiber architecture in the cardiovascular, musculoskeletal, ocular, and dermal system. In this study, we utilized Raman microspectroscopy in combination with principal component analysis (PCA) to analyze the molecular consequences of fibrillin-1 deficiency in skin of a mouse model (GT8) of Marfan syndrome. In addition, full-thickness skin models incorporating murine wild-type and Fbn1 fibroblasts as well as human HaCaT keratinocytes were generated and analyzed. Skin models containing GT8 fibroblasts showed an altered epidermal morphology when compared to wild-type models indicating a new role for fibrillin-1 in dermal-epidermal crosstalk. Obtained Raman spectra together with PCA allowed to discriminate between healthy and deficient microfibrillar networks in murine dermis and skin models. Interestingly, results obtained from GT8 dermis and skin models showed similar alterations in molecular signatures triggered by fibrillin-1 deficiency such as amide III vibrations and decreased levels of glycan vibrations. Overall, this study indicates that Raman microspectroscopy has the potential to analyze subtle changes in fibrillin-1 microfibrils and elastic fiber networks. Therefore Raman microspectroscopy may be utilized as a non-invasive and sensitive diagnostic tool to identify connective tissue disorders and monitor their disease progression. STATEMENT OF SIGNIFICANCE: Mutations in building blocks of the fibrillin microfibril/ elastic fiber network manifest in disease conditions such as aneurysms, emphysema or lax skin. Understanding how structural changes induced by fibrillin-1 mutation impact the architecture of fibrillin microfibrils, which then translates into an altered activation state of targeted growth factors, represents a huge challenge in elucidating the genotype-phenotype correlations in connective tissue disorders such as Marfan syndrome. This study shows that Raman microspectroscopy is able to reveal structural changes in fibrillin-1 microfibrils and elastic fiber networks and to discriminate between normal and diseased networks in vivo and in vitro. Therefore Raman microspectroscopy may be utilized as a non-invasive and sensitive diagnostic tool to identify connective tissue disorders and monitor their disease progression.
[Mh] Termos MeSH primário: Diagnóstico por Computador/métodos
Fibrilina-1/análise
Síndrome de Marfan/diagnóstico
Dermatopatias/diagnóstico
Pele/química
Análise Espectral Raman/métodos
[Mh] Termos MeSH secundário: Algoritmos
Animais
Biomarcadores/análise
Síndrome de Marfan/metabolismo
Camundongos
Análise de Componente Principal
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
Pele/patologia
Dermatopatias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Fibrillin-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161214
[St] Status:MEDLINE



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