{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:02:38Z","timestamp":1789538558266,"version":"build-2803163510"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Calcific aortic valve disease (CAVD) lacks effective pharmacotherapies. Although small extracellular vesicles (sEVs) are established mediators of cellular communication, how they translate oscillatory shear stress (OSS) into pro-calcific signals through endothelial-interstitial crosstalk remains unknown. This study aimed to delineate a complete mechanosensitive pathway by which sEVs drive aortic valve calcification (AVC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>Using circRNA microarray sequencing, we identified circILRUN as the most markedly upregulated circRNA in sEVs from OSS-stimulated human valvular endothelial cells (hVECs). Endothelial-derived sEVs delivered circILRUN to human valvular interstitial cells (hVICs) and promoted osteogenic reprogramming of hVICs. Genetic ablation of circILRUN attenuated AVC in two independent mouse models, improving echocardiographic parameters and reducing calcium deposition. Mechanistically, circILRUN acted as a protein scaffold that recruited USP11 to NAT10, thereby stabilizing NAT10 via suppression of K48-linked ubiquitination. Integrated N4-acetylcytidine (ac4C) acetylome and transcriptome analyses identified CD36 as a key downstream target, with NAT10 catalyzing ac4C modification within its coding sequence to enhance CD36 mRNA stability and translation. Therapeutically, pharmacological inhibition of NAT10 reversed the pro-calcific effects of circILRUN in vitro and ameliorated AVC in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study delineates a novel OSS induced sEV-circILRUN-NAT10-CD36 axis that integrates mechanical stress, epitranscriptomic regulation to drive AVC. These findings not only elucidate a fundamental mechanotransduction pathway in CAVD but also identify NAT10 as a candidate therapeutic target for clinical intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag205","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:58:39Z","timestamp":1789473519000},"source":"Crossref","is-referenced-by-count":0,"title":["Oscillatory shear stress-induced endothelial extracellular vesicles exacerbate aortic valve calcification"],"prefix":"10.1093","author":[{"given":"Shiqi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Xu","sequence":"additional","affiliation":[{"name":"Liver Transplant Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Wuhan , 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengfeng","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoshao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5103-9622","authenticated-orcid":false,"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Chongqing Hospital, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology\uff0cMinda Hospital of Hubei Minzu University , Enshi ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture , Enshi, 445000, Hubei ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Jin","sequence":"additional","affiliation":[{"name":"Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]},{"name":"Department of Urology, The Second Xiangya Hospital, Central South University , Changsha, 410011 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1241-3158","authenticated-orcid":false,"given":"Tingwen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430022 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,16]]},"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvag205\/71101987\/cvag205.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvag205\/71101987\/cvag205.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:09:36Z","timestamp":1789535376000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/advance-article\/doi\/10.1093\/cvr\/cvag205\/8798717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvag205","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]},"article-number":"cvag205"}}