title: Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin II-Induced Aortic Aneurysm and Atherosclerosis.
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.
  
  
  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 inSOSTTg.ApoE-/-mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost andSOSTTg.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/β-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas ofSOSTTg.ApoE-/-mice. SOST expression was downregulated and the wingless-type mouse mammary virus integration site/β-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.
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Smriti Murali
authors.initials: SM
authors.lastname: Krishna
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Sai-Wang
authors.initials: SW
authors.lastname: Seto
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Roby J
authors.initials: RJ
authors.lastname: Jose
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Jiaze
authors.initials: J
authors.lastname: Li
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Susan K
authors.initials: SK
authors.lastname: Morton
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Erik
authors.initials: E
authors.lastname: Biros
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Yutang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Vianne
authors.initials: V
authors.lastname: Nsengiyumva
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Jan H N
authors.initials: JH
authors.lastname: Lindeman
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rush
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.).
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
authors.affiliation: 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 Science and Health, Western Sydney University, Campbelltown, NSW, Australia (S.-W.S.); School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia (Y.W.); Department of Vascular and Transplant Surgery, Leiden University Medical Center, The Netherlands (J.H.N.L.); Physical and Life Sciences Division, Lawrence Livermore National Laboratory, CA (G.G.L.); Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia (C.M.R.); Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia (J.M.C.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Queensland, Australia (J.G.). jonathan.golledge@jcu.edu.au.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000008:administration & dosage*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D066253:Vascular Remodeling / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C422903:SOST protein, human; C486030:Sost protein, mouse; D000804:Angiotensin II
keywords: DNA methylation; aortic aneurysm; apolipoprotein E-null mouse; atherosclerosis; epigenetics; sclerostin