{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T14:17:49Z","timestamp":1782224269535,"version":"3.54.5"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81270298"],"award-info":[{"award-number":["81270298"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570247"],"award-info":[{"award-number":["81570247"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81627802"],"award-info":[{"award-number":["81627802"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900442"],"award-info":[{"award-number":["81900442"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2019YFA0210100"],"award-info":[{"award-number":["2019YFA0210100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012246","name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012246","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shuang Chuang Tuan Dui Award of the Jiangsu Province of China"},{"name":"Natural Science Foundation of Jiangsu Province for Youth","award":["BK20141024"],"award-info":[{"award-number":["BK20141024"]}]},{"name":"Natural Science Research in Universities of Jiangsu Province","award":["18KJB320005"],"award-info":[{"award-number":["18KJB320005"]}]},{"name":"Postgraduate Research & Practice Innovation Program of Jiangsu Province","award":["KYCX19_1154"],"award-info":[{"award-number":["KYCX19_1154"]}]},{"name":"Assistant Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine"},{"DOI":"10.13039\/501100010257","name":"Collaborative Innovation Center for Cardiovascular Disease Translational Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010257","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Aortic valve calcification is more prevalent in chronic kidney disease accompanied by hypercalcemia. Secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) is a regulator of BMP2 signalling, but the role of SMOC1 in aortic valve calcification under different conditions has not been studied. This study aimed to investigate the roles of SMOC1 in aortic valve calcification under normal and high calcium conditions, focusing on the effects on aortic valve interstitial cells (AVICs).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>SMOC1 was expressed by aortic valve endothelial cells and secreted into the extracellular matrix in non-calcific valves and downregulated in calcific aortic valves. In vitro studies demonstrated that HUVEC secreted SMOC1 could enter the cytoplasm of AVICs. Overexpression of SMOC1 attenuated warfarin-induced AVIC calcification but promoted high calcium\/phosphate or vitamin D-induced AVIC and aortic valve calcification by regulating BMP2 signalling both in vitro and in vivo. Co-immunoprecipitation revealed that SMOC1 binds to BMP receptor II (BMPR-II) and inhibits BMP2-induced phosphorylation of p38 (p-p38) via amino acids 372\u2013383 of its EF-hand calcium-binding domain. Inhibition of p-p38 by the p38 inhibitor SB203580 blocked the effects of SMOC1 on BMP2 signalling and AVIC calcification induced by high calcium\/phosphate medium. In high-calcium-treated AVICs, SMOC1 lost its ability to bind to BMPR-II, but not to caveolin-1, promoting p-p38 and cell apoptosis due to increased expression of BMPR-II and enhanced endocytosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These observations support that SMOC1 works as a dual-directional modulator of AVIC calcification by regulating p38-dependent BMP2 signalling transduction according to different extracellular calcium concentrations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvab107","type":"journal-article","created":{"date-parts":[[2021,3,21]],"date-time":"2021-03-21T12:06:54Z","timestamp":1616328414000},"page":"913-928","source":"Crossref","is-referenced-by-count":21,"title":["SPARC-related modular calcium binding 1 regulates aortic valve calcification by disrupting BMPR-II\/p-p38 signalling"],"prefix":"10.1093","volume":"118","author":[{"given":"Yaqing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7498-6189","authenticated-orcid":false,"given":"Anning","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqing","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9895-7369","authenticated-orcid":false,"given":"Rong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First People\u2019s Hospital of Changzhou, 185 Juqian Street, Changzhou 213004, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0833-0445","authenticated-orcid":false,"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangqing","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China"},{"name":"State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing 210029, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"2022022108492296300_cvab107-B1","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/S0735-1097(96)00563-3","article-title":"Clinical factors associated with calcific aortic valve disease. 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