{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:53:34Z","timestamp":1790790814697,"version":"4.1.0"},"reference-count":19,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Impaired sarcoplasmic reticular Ca\n              <jats:sup>2+<\/jats:sup>\n              uptake resulting from decreased sarcoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              -ATPase type 2a (SERCA2a) expression or activity is a characteristic of heart failure with its associated ventricular arrhythmias. Recent attempts at gene therapy of these conditions explored strategies enhancing\n              <jats:italic>SERCA2a<\/jats:italic>\n              expression and the activity as novel approaches to heart failure management. We here explore the role of Pak1 in maintaining ventricular Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis and electrophysiological stability under both normal physiological and acute and chronic \u03b2-adrenergic stress conditions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Mice with a cardiomyocyte-specific\n              <jats:italic>Pak1<\/jats:italic>\n              deletion (\n              <jats:italic>Pak1<\/jats:italic>\n              <jats:sup>cko<\/jats:sup>\n              ), but not controls (\n              <jats:italic>Pak1<\/jats:italic>\n              <jats:sup>f\/f<\/jats:sup>\n              ), showed high incidences of ventricular arrhythmias and electrophysiological instability during either acute \u03b2-adrenergic or chronic \u03b2-adrenergic stress leading to hypertrophy, induced by isoproterenol. Isolated\n              <jats:italic>Pak1<\/jats:italic>\n              <jats:sup>cko<\/jats:sup>\n              ventricular myocytes correspondingly showed aberrant cellular Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis.\n              <jats:italic>Pak1<\/jats:italic>\n              <jats:sup>cko<\/jats:sup>\n              hearts showed an associated impairment of SERCA2a function and downregulation of SERCA2a mRNA and protein expression. Further explorations of the mechanisms underlying the altered transcriptional regulation demonstrated that exposure to control\n              <jats:italic>Ad-shC2<\/jats:italic>\n              virus infection increased SERCA2a protein and mRNA levels after phenylephrine stress in cultured neonatal rat cardiomyocytes. This was abolished by the Pak1-knockdown in\n              <jats:italic>Ad-shPak1<\/jats:italic>\n              \u2013infected neonatal rat cardiomyocytes and increased by constitutive overexpression of active Pak1 (\n              <jats:italic>Ad-CAPak1<\/jats:italic>\n              ). We then implicated activation of serum response factor, a transcriptional factor well known for its vital role in the regulation of cardiogenesis genes in the Pak1-dependent regulation of SERCA2a.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              These findings indicate that Pak1 is required to maintain ventricular Ca\n              <jats:sup>2+<\/jats:sup>\n              homeostasis and electrophysiological stability and implicate Pak1 as a novel regulator of cardiac SERCA2a through a transcriptional mechanism.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.113.001198","type":"journal-article","created":{"date-parts":[[2014,9,13]],"date-time":"2014-09-13T04:11:57Z","timestamp":1410581517000},"page":"938-948","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Pak1 Is Required to Maintain Ventricular Ca\n            <sup>2+<\/sup>\n            Homeostasis and Electrophysiological Stability Through SERCA2a Regulation in Mice"],"prefix":"10.1161","volume":"7","author":[{"given":"Yanwen","family":"Wang","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoyee","family":"Tsui","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunbo","family":"Ke","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Shi","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yatong","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Davies","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Cartwright","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Venetucci","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henggui","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek A.","family":"Terrar","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.-H.","family":"Huang","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. John","family":"Solaro","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Lei","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Y.W., D.A.T., M.L.); Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences (Y.W., H.T., Y.L., L.D., E.J.C., L.V., M.L.), Faculty of Life Science (X.W.), School of Physics and Astronomy (H.Z.), University of Manchester, Manchester, United Kingdom; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago (Y.K., R.J.S.); Department of Cardiovascular Diseases, Union..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62834"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2008.02.005"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.111.022889"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2009.01.013"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10407"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.111.048785"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000111522.02730.56"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000266742.51389.a4"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2007.09.013"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00386.2006"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.04.014"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(03)00110-X"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90579-5"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104934200"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.280.4.H1782"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000204575.94040.d1"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.05.004"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/circep.109.863118"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/circep.110.961615"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.113.001198","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:54:09Z","timestamp":1715558049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.113.001198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,10]]}},"alternative-id":["10.1161\/CIRCEP.113.001198"],"URL":"https:\/\/doi.org\/10.1161\/circep.113.001198","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10]]},"assertion":[{"value":"2013-10-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-08-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-09-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}