{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T07:04:11Z","timestamp":1793343851312,"version":"4.5.0"},"reference-count":72,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,4,11]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Aortic aneurysm\/dissection (AAD) is a life-threatening disease lacking effective pharmacological treatment. Protein ubiquitination plays a pivotal role in cardiovascular diseases. However, the possible contribution of the E3 ubiquitin ligase March2 (membrane-associated RING [really interesting new gene] finger protein 2) to the cause of AAD remains elusive.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Integrated single-cell RNA sequencing analysis was conducted in human AAD tissues. Based on the screening results, we generated a mouse line of smooth muscle cell\u2013specific March2 knockout. \u03b2-Aminopropionitrile monofumarate was used to establish AAD. Cleavage under targets and tagmentation and cleavage under targets and tagmentation\u2013quantitative polymerase chain reaction were performed to identify possible target genes for histone H3K18 lactylation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              March2 expression was downregulated in aorta from patients with AAD or \u03b2-aminopropionitrile monofumarate\u2013induced AAD mice. \u03b2-Aminopropionitrile monofumarate\u2013induced AAD was significantly accentuated in March2 global (March2\n              <jats:sup>\u2013\/\u2013<\/jats:sup>\n              ) and vascular smooth muscle cell\u2013specific deletion (March2\n              <jats:sup>fl\/fl<\/jats:sup>\n              ; Tagln\n              <jats:sup>Cre<\/jats:sup>\n              ) mice, whereas the AAD pathology was rescued by rAAV9-SM22\u03b1 (smooth muscle 22\u03b1)-March2 (recombinant adeno-associated virus serotype 9 expressing Flag-tagged March2 under SM22\u03b1 promoter). March2 interacted with PKM2 (pyruvate kinase M2) to promote K33-linked polyubiquitination. Deficiency of March2 lessened PKM2 dimer-to-tetramer conversion in AAD and overtly exacerbated AAD-induced histone H3K18 lactylation in vascular smooth muscle cells by fostering glucose metabolism reprogramming, thereby promoting p53-driven apoptotic transcriptional response\u2014a hallmark of AAD pathogenesis. TEPP-46 (tetraethyl pyrophosphate), a PKM2-specific activator, pronouncedly alleviated March2 deficiency\u2013deteriorated AAD pathology.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Our findings demonstrated that March2 is a novel endogenous defender that prevents AAD by inhibiting vascular smooth muscle cell apoptosis, suggesting that March2 represents a potential therapeutic target for AAD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325049","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T09:01:03Z","timestamp":1741856463000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["March2 Alleviates Aortic Aneurysm\/Dissection by Regulating PKM2 Polymerization"],"prefix":"10.1161","volume":"136","author":[{"given":"Yiran E.","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuolin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"Department of Vascular Surgery (Z.L., Lixin Wang), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7142-456X","authenticated-orcid":true,"given":"Litao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. 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Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3535-5250","authenticated-orcid":true,"given":"Jie","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0460-6742","authenticated-orcid":true,"given":"Shengjun","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6385-3201","authenticated-orcid":true,"given":"Yayu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People\u2019s Hospital), Guangdong, China (Y.W., Q.Z.)."},{"name":"Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, Guangdong (Y.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-8537","authenticated-orcid":true,"given":"Qijun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People\u2019s Hospital), Guangdong, China (Y.W., Q.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-5472","authenticated-orcid":true,"given":"Rongjun","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (R.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6766-5432","authenticated-orcid":true,"given":"Ling","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheyun","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"Department of Vascular Surgery (Z.L., Lixin Wang), Zhongshan Hospital, Fudan University, China."},{"name":"Vascular Surgery Institute of Fudan University, Shanghai, China (Z.L., Lixin Wang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1379-3906","authenticated-orcid":true,"given":"Lixin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"Department of Vascular Surgery (Z.L., Lixin Wang), Zhongshan Hospital, Fudan University, China."},{"name":"Vascular Surgery Institute of Fudan University, Shanghai, China (Z.L., Lixin Wang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0275-0783","authenticated-orcid":true,"given":"Jun","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"State Key Laboratory of Cardiovascular Diseases (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., Z.L., Lixin Wang, J.G., J.R., Y.Z.), Zhongshan Hospital, Fudan University, China."},{"name":"National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. Wu, H.C., T.Z., J.L., S.X., L.L., J.G., J.R., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China (Y.E.L., S.L., Litao Wang, Y.D., L. 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