{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T03:15:07Z","timestamp":1794021307171,"version":"4.8.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,4,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Calcium (Ca\n              <jats:sup>2+<\/jats:sup>\n              ) is a key regulator of energy metabolism. Impaired Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca\n              <jats:sup>2+<\/jats:sup>\n              uniporter (MCU) in chronic stress-induced pathological cardiac remodeling.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              MCU knockout or transgenic mice were infused with isoproterenol (ISO; 10 mg\/kg per day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nmol\/L, 48 hours). Intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Chronic administration of the \u03b2-adrenergic receptor agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca\n              <jats:sup>2+<\/jats:sup>\n              concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. It is interesting that ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout mice. Cardiomyocytes from knockout mice or overexpressing a dominant negative MCU exhibited defective intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin kinase II \u03b4B (CaMKII\u03b4B) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKII\u03b4B phosphorylated CREB (cAMP-response element binding protein), which bound the\n              <jats:italic>Mcu<\/jats:italic>\n              promoter to enhance\n              <jats:italic>Mcu<\/jats:italic>\n              gene transcription.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              The \u03b2-adrenergic receptor\/CaMKII\u03b4B\/CREB pathway upregulates\n              <jats:italic>Mcu<\/jats:italic>\n              gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis and cardiomyocyte viability.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.055841","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T19:21:55Z","timestamp":1644952915000},"page":"1067-1083","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":114,"title":["Elevated MCU Expression by CaMKII\u03b4B Limits Pathological Cardiac Remodeling"],"prefix":"10.1161","volume":"145","author":[{"given":"Pei","family":"Wang","sequence":"first","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangcheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiqian","family":"Xu","sequence":"additional","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanguo","family":"Xin","sequence":"additional","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1337-105X","authenticated-orcid":true,"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology (Y.L., H.Z., H.X., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8967-1219","authenticated-orcid":true,"given":"Huiliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."},{"name":"Department of Laboratory Medicine and Pathology (Y.L., H.Z., H.X., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7388-8376","authenticated-orcid":true,"given":"Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haodong","family":"Xu","sequence":"additional","affiliation":[{"name":"Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shey-Shing","family":"Sheu","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 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