{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T22:09:48Z","timestamp":1791670188970,"version":"4.3.4"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,8,15]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Smooth muscle cell\u2013specific and endothelial cell\u2013specific Best3 knockout mice (Best3\n              <jats:sup>SMKO<\/jats:sup>\n              and Best3\n              <jats:sup>ECKO<\/jats:sup>\n              , respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3\n              <jats:sup>SMKO<\/jats:sup>\n              but not Best3\n              <jats:sup>ECKO<\/jats:sup>\n              mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2\/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2\/3 prevented AD progression in angiotensin II\u2013infused Best3\n              <jats:sup>SMKO<\/jats:sup>\n              and ApoE\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2\/3 degradation. Best3\u2013MEKK2\/3 signaling represents a novel therapeutic target for AD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.122.063029","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T09:00:17Z","timestamp":1684486817000},"page":"589-606","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2\/3\u2013MAPK Signaling to Trigger Spontaneous Aortic Dissection"],"prefix":"10.1161","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7823-1679","authenticated-orcid":true,"given":"Ting-Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"Program of Cardiovascular Research, The Eighth Affiliated Hospital (T.-T.Z., H.H., J.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China."},{"name":"Department of Pharmacology, Cardiac and Cerebrovascular Research Center (T.-T.Z., Q.-Q.L., X.G., X.Z., Z.-Y.Z., T.W., J.-Y.S., Z.-M.L., W.-L.P., L.-K.X., Y.-L.H., Z.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China."},{"name":"Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (T.-T.Z., Y.H., H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Qing","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebrovascular Research Center (T.-T.Z., Q.-Q.L., X.G., X.Z., Z.-Y.Z., T.W., J.-Y.S., Z.-M.L., W.-L.P., L.-K.X., Y.-L.H., Z.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2487-8663","authenticated-orcid":true,"given":"Jie","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China (J.H., X.-P.F.)."},{"name":"Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases (J.H.), NHC Key Laboratory of Assisted Circulation (Sun Yat-Sen University), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebrovascular Research Center (T.-T.Z., Q.-Q.L., X.G., X.Z., Z.-Y.Z., T.W., J.-Y.S., Z.-M.L., W.-L.P., L.-K.X., Y.-L.H., Z.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4914-0488","authenticated-orcid":true,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebrovascular Research Center (T.-T.Z., Q.-Q.L., X.G., X.Z., Z.-Y.Z., T.W., J.-Y.S., Z.-M.L., W.-L.P., L.-K.X., Y.-L.H., Z.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China (T.-T.Z., Y.H., H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Yue","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebrovascular Research Center (T.-T.Z., Q.-Q.L., X.G., X.Z., Z.-Y.Z., T.W., J.-Y.S., Z.-M.L., W.-L.P., L.-K.X., Y.-L.H., Z.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1779-2986","authenticated-orcid":true,"given":"Rui-Xin","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People\u2019s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (R.-X.F., C.-X.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cardiac and Cerebrovascular Research Center (T.-T.Z., Q.-Q.L., X.G., X.Z., Z.-Y.Z., T.W., J.-Y.S., Z.-M.L., W.-L.P., L.-K.X., Y.-L.H., Z.-G.Z.), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 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