{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:20:03Z","timestamp":1791840003099,"version":"4.3.4"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"23","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,6,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiac hypertrophy, as an important pathological change, contributes to heart failure. Recent studies indicate that the mitochondria-associated endoplasmic reticulum membranes (MAMs) play key roles in this pathological process. However, the molecular mechanism remains unclear. This study aims to elucidate the effects and mechanisms of MAM-resident FMO2 (flavin-containing monooxygenase 2) in cardiac hypertrophy and heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We performed bulk RNA-sequencing analysis using heart tissue from patients with cardiac hypertrophy and carried out MAM-targeted mass spectrometry analysis using heart tissue from a mouse model of pathological cardiac hypertrophy. In vitro cell culture using neonatal rat cardiomyocytes was used to study how MAMs formation affected cardiomyocyte functions. By generating different genetic mouse models combined with using adeno-associated virus 9 under the cardiac troponin T promoter techniques, we further investigated and confirmed the effects of MAM structure changes on cardiac hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We detected an unexpected component of MAMs structure, which was the FMO2, an endoplasmic reticulum\u2013resident protein. FMO2 levels decreased during pathological cardiac hypertrophy. The deletion and overexpression of FMO2 can either worsen or prevent the pathological heart failure progression in vivo, respectively. Our data further demonstrated that FMO2 localizes to MAM structure, where it binds to inositol 1,4,5-trisphosphate type 2 receptor (IP3R2) as a component of the IP3R2\u2013Grp75 (glucose-regulated protein 75)\u2013VDAC1 (voltage-dependent anion channel protein 1) complex, maintaining endoplasmic reticulum\u2013mitochondria contact and regulating mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signaling for bioenergetics. Last, we showed that a synthetic peptide-enhancing endoplasmic reticulum\u2013mitochondria contact promoted Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transfer and prevented pathological cardiac hypertrophy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings reveal a key role of FMO2 in myocardial hypertrophy and that FMO2 plays a pivotal role in maintaining MAM structure and function, which may represent a novel mechanism and therapeutic target for cardiac hypertrophy and heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.072661","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T14:00:21Z","timestamp":1749477621000},"page":"1667-1685","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["FMO2 Prevents Pathological Cardiac Hypertrophy by Maintaining the ER-Mitochondria Association Through Interaction With IP3R2-Grp75-VDAC1"],"prefix":"10.1161","volume":"151","author":[{"given":"Changchen","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7357-9450","authenticated-orcid":true,"given":"Jingyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianpeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changle","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0986-7877","authenticated-orcid":true,"given":"Jinliang","family":"Nan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., 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Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanna","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8681-3296","authenticated-orcid":true,"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., 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X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyuan","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."},{"name":"State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., J.W., W.Z., X.H.)."},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, China (C.X., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., X.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (C.X., C.W., J.W., X.W., C.K., J.N., H.D., Y.X., Y.S., J.Z., C.N., Q.L., J.L., S.S., H.C., J.C., T.Z., J.C., Q.S., J.W., W.Z., 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