{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:03:02Z","timestamp":1788447782974,"version":"build-2803163510"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,5,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias, and increased risk of sudden cardiac death. The guideline for management of ARVC in patients is to improve quality of life by reducing arrhythmic symptoms and to prevent sudden cardiac death. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Using protein mass spectrometry analyses, we identified that integrin \u03b21 is downregulated in ARVC hearts without changes to Ca\n              <jats:sup>2+<\/jats:sup>\n              -handling proteins. As adult cardiomyocytes express only the \u03b21D isoform, we generated a cardiac specific \u03b21D knockout mouse model and performed functional imaging and biochemical analyses to determine the consequences of integrin \u03b21D loss on function in the heart in vivo and in vitro.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Integrin \u03b21D deficiency and RyR2 Ser-2030 hyperphosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found that purified integrin \u03b21D protein could stabilize RyR2 function by decreasing RyR2 open probability, mean open time, and increasing mean close time. Also, \u03b21D knockout mice exhibited normal cardiac function and morphology but presented with catecholamine-sensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca\n              <jats:sup>2+<\/jats:sup>\n              handling in \u03b21D knockout cardiomyocytes. Mechanistically, we revealed that loss of DSP (desmoplakin) induces integrin \u03b21D deficiency in ARVC mediated through an ERK1\/2 (extracellular signal\u2013regulated kinase 1 and 2)\u2013fibronectin\u2013ubiquitin\/lysosome pathway.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our data suggest that integrin \u03b21D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.043504","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T18:39:32Z","timestamp":1584556772000},"page":"1477-1493","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":57,"title":["Integrin \u03b21D Deficiency\u2013Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in Arrhythmogenic Right Ventricular Cardiomyopathy"],"prefix":"10.1161","volume":"141","author":[{"given":"Yihui","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.W., C.L., X.C., C.C., M.L., S.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.W., C.L., X.C., C.C., M.L., S.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, and State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Heilongjiang, China (L.S., Z.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyu","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.W., C.L., X.C., C.C., M.L., S.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.W., C.L., X.C., C.C., M.L., S.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City (B.C., D.D.H., L.-S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane D.","family":"Hall","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City (B.C., D.D.H., L.-S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenwei","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, and State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Heilongjiang, China (L.S., Z.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjie","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Y.W., C.L., X.C., C.C., M.L., S.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Fujian Institute of Coronary Heart Disease, Fujian Medical University Union Hospital, China (J.H.)."},{"name":"Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, China 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