Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin II-Induced Aortic Aneurysm and Atherosclerosis

Smriti Murali Krishna; Sai-Wang Seto; Roby J Jose; Jiaze Li; Susan K Morton; Erik Biros; Yutang Wang; Vianne Nsengiyumva; Jan H N Lindeman; Gabriela G Loots; Catherine M Rush; Jeffrey M Craig; Jonathan Golledge

doi:10.1161/ATVBAHA.116.308723

Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin II-Induced Aortic Aneurysm and Atherosclerosis

Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):553-566. doi: 10.1161/ATVBAHA.116.308723. Epub 2016 Dec 22.

Affiliations

¹ 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.).
² 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.

PMID: 28062506
DOI: 10.1161/ATVBAHA.116.308723

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 (SOST^Tg .ApoE^-/-) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOST^Tg .ApoE^-/- mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOST^Tg .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 of SOST^Tg .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.

Keywords: DNA methylation; aortic aneurysm; apolipoprotein E-null mouse; atherosclerosis; epigenetics; sclerostin.

MeSH terms

Adaptor Proteins, Signal Transducing
Aged
Aged, 80 and over
Angiotensin II*
Animals
Aorta, Abdominal / drug effects
Aorta, Abdominal / metabolism
Aorta, Abdominal / pathology
Aorta, Thoracic / drug effects
Aorta, Thoracic / metabolism
Aorta, Thoracic / pathology
Aortic Aneurysm / chemically induced
Aortic Aneurysm / genetics
Aortic Aneurysm / metabolism
Aortic Aneurysm / prevention & control*
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Atherosclerosis / chemically induced
Atherosclerosis / genetics
Atherosclerosis / metabolism
Atherosclerosis / prevention & control*
Bone Morphogenetic Proteins / genetics
Bone Morphogenetic Proteins / metabolism*
Cells, Cultured
Cytokines / metabolism
Epigenesis, Genetic / drug effects
Extracellular Matrix / metabolism
Female
Genetic Markers / genetics
Genetic Predisposition to Disease
Glycoproteins / administration & dosage*
Humans
Intercellular Signaling Peptides and Proteins
Macrophages / drug effects
Macrophages / metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Muscle, Smooth, Vascular / drug effects*
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / drug effects*
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology
Phenotype
Vascular Remodeling / drug effects
Wnt Signaling Pathway / drug effects*

Substances

Adaptor Proteins, Signal Transducing
Apolipoproteins E
Bone Morphogenetic Proteins
Cytokines
Genetic Markers
Glycoproteins
Intercellular Signaling Peptides and Proteins
SOST protein, human
Sost protein, mouse
Angiotensin II