{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:38:36Z","timestamp":1790444316500,"version":"4.1.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100003009","name":"Noncommunicable Chronic Diseases-National Science and Technology","doi-asserted-by":"publisher","award":["2024ZD0526900"],"award-info":[{"award-number":["2024ZD0526900"]}],"id":[{"id":"10.13039\/501100003009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007229","name":"Clinical Research Special Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007229","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003347","name":"Fudan University","doi-asserted-by":"publisher","award":["KY2024177"],"award-info":[{"award-number":["KY2024177"]}],"id":[{"id":"10.13039\/501100003347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["T2288101"],"award-info":[{"award-number":["T2288101"]}],"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":["82130010"],"award-info":[{"award-number":["82130010"]}],"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":["82100355"],"award-info":[{"award-number":["82100355"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Aldehyde dehydrogenase 2 (ALDH2) is a critical mitochondrial enzyme responsible for aldehyde detoxification and maintenance of redox homeostasis. The rs671 variant, a prevalent loss-of-function mutation in East Asian populations (30\u201350% carrier frequency), diminishes ALDH2 enzymatic activity by 60\u201390% and is associated with elevated thrombotic risk. Although platelet activation is known to play a central role in thrombosis formation, the specific contribution of ALDH2 to this process has not been fully elucidated. This study was designed to investigate the functional role of ALDH2 in platelet activation and thrombus formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Platelet activation and thrombus formation were assessed in wild-type (WT), systemic Aldh2-knockout (Aldh2\u2212\/\u2212), and systemic Aldh2E487K\/E487K-knockin mice, as well as patients with coronary artery disease (CAD) and healthy volunteers. Mechanistic studies were performed using immunoprecipitation, mass spectrometry, and RNA sequencing. Nicotinamide adenine dinucleotide (NAD+) supplementation was evaluated for its potential to mitigate the effects of ALDH2 variant. Patients with CAD carrying the ALDH2 rs671 variant exhibited enhanced platelet reactivity to collagen compared with those without the variant. Collagen-induced platelet aggregation, granule release, and integrin \u03b1IIb\u03b23 activation were significantly enhanced in Aldh2\u2212\/\u2212 mice compared with WT mice. Mechanistically, ALDH2 deficiency disrupted mitochondrial complex I assembly and function. This increased reactive oxygen species production via the collagen\/glycoprotein VI (GPVI)\/NAD phosphate oxidase 1 (NOX1) pathway and enhanced platelet reactivity. Similar results were observed in Aldh2E487K\/E487K-knockin mice. NAD+ supplementation effectively counteracted ALDH2 variant-induced platelet hyperreactivity and thrombosis in both mice and human subjects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The ALDH2 rs671 variant enhances collagen-induced platelet activation and thrombosis by impairing mitochondrial complex I assembly and function. NAD+ supplementation offers a promising strategy to mitigate thrombotic risk in individuals carrying this variant.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf194","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T12:35:55Z","timestamp":1761568555000},"page":"2246-2259","source":"Crossref","is-referenced-by-count":3,"title":["<i>ALDH2<\/i>\n                    rs671 variant enhances platelet activation and thrombosis by disrupting mitochondrial complex I assembly"],"prefix":"10.1093","volume":"121","author":[{"given":"Haoxuan","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maieryemu","family":"Waresi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luning","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"National Clinical Research Center for Interventional Medicine , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajie","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Zhongshan Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5682-4995","authenticated-orcid":false,"given":"Si","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"National Clinical Research Center for Interventional Medicine , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032 ,","place":["China"]},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences , 180 Fenglin Road, Shanghai 200032 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Biomedical Sciences, Fudan University , 180 Fenglin Road, Shanghai 200032 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"2025112201570566600_cvaf194-B1","first-page":"785","article-title":"Thrombosis and platelets: an update","volume":"38","author":"Koupenova","year":"2017","journal-title":"Eur Heart J"},{"key":"2025112201570566600_cvaf194-B2","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990\u20132019: update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"2025112201570566600_cvaf194-B3","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41569-018-0110-0","article-title":"Platelet biology and functions: new concepts and clinical perspectives","volume":"16","author":"van der 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