Your browser doesn't support javascript.
loading
Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin II-Induced Aortic Aneurysm and Atherosclerosis.
Krishna, Smriti Murali; Seto, Sai-Wang; Jose, Roby J; Li, Jiaze; Morton, Susan K; Biros, Erik; Wang, Yutang; Nsengiyumva, Vianne; Lindeman, Jan H N; Loots, Gabriela G; Rush, Catherine M; Craig, Jeffrey M; Golledge, Jonathan.
Afiliação
  • Krishna SM; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Seto SW; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Jose RJ; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Li J; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Morton SK; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Biros E; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Wang Y; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Nsengiyumva V; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Lindeman JH; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Loots GG; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Rush CM; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Craig JM; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
  • Golledge J; From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia (S.M.K., S.-W.S., R.J.J., J.L., S.K.M., E.B., Y.W., V.N., J.G.); National Institute of Complementary Medicine (NICM), School of
Arterioscler Thromb Vasc Biol ; 37(3): 553-566, 2017 Mar.
Article em En | MEDLINE | ID: mdl-28062506
ABSTRACT

OBJECTIVE:

Sclerostin (SOST) has been identified as an important regulator of bone formation; however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human samples, a mouse model, and in vitro investigations. APPROACH AND

RESULTS:

SOST protein was downregulated in human and mouse AA samples compared with controls. Transgenic introduction of human SOST in apolipoprotein E-deficient (ApoE-/-) mice (SOSTTg .ApoE-/-) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOSTTg .ApoE-/- mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOSTTg .ApoE-/- mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/ß-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOSTTg .ApoE-/- mice. SOST expression was downregulated and the wingless-type mouse mammary virus integration site/ß-catenin pathway was activated in human AA samples. The cytosine-phosphate-guanine islands in the SOST gene promoter showed significantly higher methylation in human AA samples compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated.

CONCLUSIONS:

This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
Assuntos
Angiotensina II; Aneurisma Aórtico/prevenção & controle; Aterosclerose/prevenção & controle; Proteínas Morfogenéticas Ósseas/metabolismo; Glicoproteínas/administração & dosagem; Músculo Liso Vascular/efeitos dos fármacos; Miócitos de Músculo Liso/efeitos dos fármacos; Via de Sinalização Wnt/efeitos dos fármacos; Proteínas Adaptadoras de Transdução de Sinal; Idoso; Idoso de 80 Anos ou mais; Animais; Aorta Abdominal/efeitos dos fármacos; Aorta Abdominal/metabolismo; Aorta Abdominal/patologia; Aorta Torácica/efeitos dos fármacos; Aorta Torácica/metabolismo; Aorta Torácica/patologia; Aneurisma Aórtico/induzido quimicamente; Aneurisma Aórtico/genética; Aneurisma Aórtico/metabolismo; Apolipoproteínas E/deficiência; Apolipoproteínas E/genética; Aterosclerose/induzido quimicamente; Aterosclerose/genética; Aterosclerose/metabolismo; Proteínas Morfogenéticas Ósseas/genética; Células Cultivadas; Citocinas/metabolismo; Epigênese Genética/efeitos dos fármacos; Matriz Extracelular/metabolismo; Feminino; Marcadores Genéticos/genética; Predisposição Genética para Doença; Humanos; Peptídeos e Proteínas de Sinalização Intercelular; Macrófagos/efeitos dos fármacos; Macrófagos/metabolismo; Masculino; Camundongos Endogâmicos C57BL; Camundongos Knockout; Camundongos Transgênicos; Músculo Liso Vascular/metabolismo; Músculo Liso Vascular/patologia; Miócitos de Músculo Liso/metabolismo; Miócitos de Músculo Liso/patologia; Fenótipo; Remodelação Vascular/efeitos dos fármacos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aneurisma Aórtico / Angiotensina II / Glicoproteínas / Proteínas Morfogenéticas Ósseas / Miócitos de Músculo Liso / Aterosclerose / Via de Sinalização Wnt / Músculo Liso Vascular Tipo de estudo: Prognostic_studies Limite: Aged80 Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aneurisma Aórtico / Angiotensina II / Glicoproteínas / Proteínas Morfogenéticas Ósseas / Miócitos de Músculo Liso / Aterosclerose / Via de Sinalização Wnt / Músculo Liso Vascular Tipo de estudo: Prognostic_studies Limite: Aged80 Idioma: En Ano de publicação: 2017 Tipo de documento: Article