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

doi:10.1161/ATVBAHA.116.308723

Title: Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin II–Induced Aortic Aneurysm and Atherosclerosis

Journal Article · Wed Mar 01 00:00:00 EST 2017 · Arteriosclerosis, Thrombosis, and Vascular Biology

DOI:https://doi.org/10.1161/ATVBAHA.116.308723· OSTI ID:1527281

Krishna, Smriti Murali ^[1]; Seto, Sai-Wang ^[2]; Jose, Roby J. ^[1]; Li, Jiaze ^[1]; Morton, Susan K. ^[1]; Biros, Erik ^[1]; Wang, Yutang ^[3]; Nsengiyumva, Vianne ^[1]; Lindeman, Jan H. N. ^[4]; Loots, Gabriela G. ^[5]; Rush, Catherine M. ^[1]; Craig, Jeffrey M. ^[6]; Golledge, Jonathan ^[7]

James Cook Univ., Townsville, QLD (Australia)
James Cook Univ., Townsville, QLD (Australia); Univ. of Western Sydney, NSW (Australia)
James Cook Univ., Townsville, QLD (Australia); Federation Univ., Ballarat, VIC (Australia)
Leiden Univ. (Netherlands)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Univ. of Melbourne (Australia)
James Cook Univ., Townsville, QLD (Australia); Townsville Hospital, Townsville, QLD (Australia)

Objective— Sclerostin (SOST) has been identified as a critical regulator of bone formation; however, it has not been previously implicated in arterial disease. The goal 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 work 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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Health and Medical Research Council

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1527281

Report Number(s):: LLNL-JRNL-698297; 829144

Journal Information:: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 37, Issue 3; ISSN 1079-5642

Publisher:: American Heart AssociationCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 114 works

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Renin-Angiotensin System and Cardiovascular Functions Wu, Chia-Hua; Mohammadmoradi, Shayan; Chen, Jeff Z. Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 38, Issue 7 https://doi.org/10.1161/atvbaha.118.311282	journal	July 2018
SM22α (Smooth Muscle 22α) Prevents Aortic Aneurysm Formation by Inhibiting Smooth Muscle Cell Phenotypic Switching Through Suppressing Reactive Oxygen Species/NF-κB (Nuclear Factor-κB) Zhong, Lintao; He, Xiang; Si, Xiaoyun Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 39, Issue 1 https://doi.org/10.1161/atvbaha.118.311917	journal	January 2019
Updates of Recent Aortic Aneurysm Research Davis, Frank M.; Daugherty, Alan; Lu, Hong S. Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 39, Issue 3 https://doi.org/10.1161/atvbaha.119.312000	journal	March 2019
Pharmacologic Management of Aneurysms Lindeman, Jan H.; Matsumura, Jon S. Circulation Research, Vol. 124, Issue 4 https://doi.org/10.1161/circresaha.118.312439	journal	February 2019
Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells Nogi, Masamichi; Satoh, Kimio; Sunamura, Shinichiro Circulation, Vol. 138, Issue 21 https://doi.org/10.1161/circulationaha.118.035648	journal	November 2018
Recombinant Klotho protein enhances cholesterol efflux of THP-1 macrophage-derived foam cells via suppressing Wnt/β-catenin signaling pathway Liu, Wei; Chen, Xiujuan; Wu, Min BMC Cardiovascular Disorders, Vol. 20, Issue 1 https://doi.org/10.1186/s12872-020-01400-9	journal	March 2020
Novel actions of sclerostin on bone Holdsworth, Gill; Roberts, Scott J.; Ke, Hua Zhu Journal of Molecular Endocrinology, Vol. 62, Issue 2 https://doi.org/10.1530/jme-18-0176	journal	February 2019

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