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., and Golledge, Jonathan (2017) Wnt signaling pathway inhibitor sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis. Arteriosclerosis, Thrombosis and Vascular Biology, 37 (3). pp. 553-566.

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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/β-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/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.

Item ID: 48842
Item Type: Article (Research - C1)
ISSN: 1524-4636
Keywords: aortic aneurysm, apolipoprotein, E-null mouse, atherosclerosis, DNA, methylation, epigenetic, sclerostin
Funders: National Health and Medical Research Council of Australia (NHMRC), Queensland Government, Townsville Hospital Private Practice Trust, James Cook University (JCU), National Heart Foundation of Australia (NHF)
Projects and Grants: NHMRC 1079369, NHMRC 1079193, NHMRC 1063476, NHMRC 1021416, NHMRC 11000967, NHMRC 1019921, NHMRC 1016349, NHF PD12B6825
Date Deposited: 04 May 2017 00:42
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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