{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:38:31Z","timestamp":1790444311324,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Myocardial ischemia-reperfusion (I\/R) injury presents a significant clinical challenge characterized by a complex pathological mechanism. The role of protein ubiquitination in I\/R injury has not been systematically investigated. Global ubiquitinome profiling was conducted to identify the potential key players in myocardial I\/R injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      The ubiquitination levels of proteins in mouse hearts subjected to either sham surgery or I\/R injury were analyzed using ubiquitinome. A combined analysis of ubiquitinome, single-cell RNA sequencing (RNA-seq), and proteomics data was employed to predict potential E3 ubiquitin ligases associated with myocardial I\/R injury. Global heterozygous 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation 1 (Hrd1) knockout, endothelial cell (EC)\u2013specific Hrd1 deficiency (Hrd1\n                      <jats:sup>f\/f<\/jats:sup>\n                      ; Cdh5\n                      <jats:sup>Cre<\/jats:sup>\n                      ), and EC-specific Hrd1 overexpression (AAV-EC-Hrd1) mice were used to assess the role of Hrd1 in myocardial I\/R injury. Mass spectrometry and immunoprecipitation were used to elucidate the interaction between Hrd1 and aldehyde dehydrogenase 2 (ALDH2). Additionally, we assessed ubiquitination and vasomotor reactivity to clarify the mechanisms by which Hrd1 regulates ALDH2 activity and EC dysfunction during I\/R injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Ubiquitinome analysis revealed that protein ubiquitination exacerbates endothelial dysfunction after myocardial I\/R injury. Integrative analysis of the ubiquitinome, proteomics, and single-cell RNA-seq revealed a significant upregulation of the E3 ubiquitin-protein ligase Hrd1 in CD45\n                      <jats:sup>+<\/jats:sup>\n                      ECs. In both humans and mice, the level of endothelial Hrd1 protein was found to increase in response to I\/R in vivo. Genetic ablation of Hrd1 significantly alleviated myocardial infarction, endothelial dysfunction, and infiltration of inflammatory cells after I\/R injury. Mechanistically, Hrd1 promoted the K33-linked polyubiquitination of ALDH2 and then inhibited the formation of its active tetramers, which reduced the apoptosis of CD45\n                      <jats:sup>+<\/jats:sup>\n                      ECs and exacerbated endothelial dysfunction through the NO\/cGMP\/PKG (nitric oxide\u2013cyclic guanosine monophosphate\u2013protein kinase G) signaling pathway. Furthermore, our findings demonstrated that pharmacological inhibition of Hrd1 robustly ameliorated myocardial I\/R injury and endothelial dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings demonstrated a previously unidentified crucial role of cardiac EC Hrd1 in myocardial I\/R injury. Hrd1 may serve as a therapeutic target for preventing myocardial I\/R injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074399","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T09:01:12Z","timestamp":1776416472000},"page":"334-353","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting E3 Ubiquitin Ligase Hrd1 Prevents Myocardial Ischemia-Reperfusion Injury Through Enhancing ALDH2 Enzymatic Activity"],"prefix":"10.1161","volume":"154","author":[{"given":"Shuolin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (S.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8007-6878","authenticated-orcid":true,"given":"Chuanyin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (C.L., M.Z., Y.L., R.H.)."},{"name":"Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China (C.L., M.Z., Y.L., R.H.)."},{"name":"Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China (C.L., M.Z., Y.L., R.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5265-2006","authenticated-orcid":true,"given":"Min","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (C.L., M.Z., Y.L., R.H.)."},{"name":"Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China (C.L., M.Z., Y.L., R.H.)."},{"name":"Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China (C.L., M.Z., Y.L., R.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingfang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran E.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., 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Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"National Clinical Research Center for Interventional Medicine, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China (S.L., T.Z., Y.E.L., C.X., J.G., Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5781-3745","authenticated-orcid":true,"given":"Hongyan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry 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