{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:21:37Z","timestamp":1792639297838,"version":"4.5.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,6,11]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Biotin-switch assay combined with liquid chromatography\u2013tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and\n              <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice infused with angiotensin II. Angiotensin II\u2013induced aortic aneurysm model and \u03b2-aminopropionitrile\u2013induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography\u2013tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and\n              <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-\u03baB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-\u03baB signaling pathway\u2013dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.123.066404","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T10:01:09Z","timestamp":1707991269000},"page":"1903-1920","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages"],"prefix":"10.1161","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1059-8256","authenticated-orcid":true,"given":"Yan","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Collaborative Innovation Center for Cardiovascular Disease 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Jiangsu, China (Y.Z., H.Z., S.Z., Z.Q., Y.H., X.Z., W.W., K.Y., L.H., S.S., F.C., L.X., Y.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Qi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Jiangsu, China (Y.Z., H.Z., S.Z., Z.Q., Y.H., X.Z., W.W., K.Y., L.H., S.S., F.C., L.X., Y.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Jiangsu, China (Y.Z., H.Z., S.Z., Z.Q., Y.H., X.Z., W.W., K.Y., L.H., S.S., F.C., L.X., Y.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Jiangsu, China (Y.Z., H.Z., S.Z., Z.Q., Y.H., X.Z., W.W., K.Y., L.H., S.S., F.C., L.X., Y.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Jiangsu, China (Y.Z., H.Z., S.Z., Z.Q., Y.H., X.Z., W.W., K.Y., L.H., S.S., F.C., L.X., 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