{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T12:38:35Z","timestamp":1723034315078},"reference-count":40,"publisher":"Portland Press Ltd.","issue":"6","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,3,30]]},"abstract":"<jats:p>Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo, and HF following experimental myocardial infarction (MI) in vivo.<\/jats:p>\n               <jats:p>Methods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca2+-regulatory genes, and induced hypertrophy without significant differences in Ca2+ transients or diastolic Ca2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo. In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF.<\/jats:p>\n               <jats:p>Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF.<\/jats:p>","DOI":"10.1042\/cs20171337","type":"journal-article","created":{"date-parts":[[2018,2,28]],"date-time":"2018-02-28T01:35:26Z","timestamp":1519781726000},"page":"641-654","update-policy":"http:\/\/dx.doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cardiac-specific inducible overexpression of human plasma membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury"],"prefix":"10.1042","volume":"132","author":[{"given":"Al\u00a0Muktafi","family":"Sadi","sequence":"first","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Talat","family":"Afroze","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.\u00a0Ahsan","family":"Siraj","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"},{"name":"Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul","family":"Momen","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"White-Dzuro","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"},{"name":"The Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorrin","family":"Zarrin-Khat","sequence":"additional","affiliation":[{"name":"Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shivalika","family":"Handa","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiwon","family":"Ban","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.\u00a0Golam","family":"Kabir","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"},{"name":"The Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria\u00a0G.","family":"Trivieri","sequence":"additional","affiliation":[{"name":"The Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Gros","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Backx","sequence":"additional","affiliation":[{"name":"Department of Biology, York University, Toronto, ON M3J-1P3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansoor","family":"Husain","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G-2C4, Canada"},{"name":"Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G-2C4, Canada"},{"name":"The Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G-2C4, Canada"},{"name":"Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5G-2C4, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, ON M5G-2C4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,3,26]]},"reference":[{"key":"2021113011041495900_B1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1007\/s11427-011-4199-1","article-title":"Ca2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps","volume":"54","author":"Cartwright","year":"2011","journal-title":"Sci. China Life Sci."},{"key":"2021113011041495900_B2","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s40291-013-0035-6","article-title":"Genetic prediction of heart failure incidence, prognosis and beta-blocker response","volume":"17","author":"Filigheddu","year":"2013","journal-title":"Mol. Diagn. Ther."},{"key":"2021113011041495900_B3","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1161\/CIRCULATIONAHA.113.004046","article-title":"The global burden of ischemic heart disease in 1990 and 2010: the global burden of disease 2010 study","volume":"129","author":"Moran","year":"2014","journal-title":"Circulation"},{"key":"2021113011041495900_B4","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1113\/expphysiol.2012.068262","article-title":"Understanding the physiology of heart failure through cellular and in vivo models-towards targeting of complex mechanisms","volume":"98","author":"Lehnart","year":"2013","journal-title":"Exp. Physiol."},{"key":"2021113011041495900_B5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation\u2013contraction coupling","volume":"415","author":"Bers","year":"2002","journal-title":"Nature"},{"key":"2021113011041495900_B6","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1161\/01.CIR.0000120390.68287.BB","article-title":"Hypertrophy of the heart: a new therapeutic target?","volume":"109","author":"Frey","year":"2004","journal-title":"Circulation"},{"key":"2021113011041495900_B7","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1146\/annurev.physiol.63.1.391","article-title":"Cytoplasmic signaling pathways that regulate cardiac hypertrophy","volume":"63","author":"Molkentin","year":"2001","journal-title":"Annu. Rev. Physiol."},{"key":"2021113011041495900_B8","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1096\/fj.02-0889com","article-title":"Hallmarks of ion channel gene expression in end-stage heart failure","volume":"17","author":"Borlak","year":"2003","journal-title":"FASEB J."},{"key":"2021113011041495900_B9","doi-asserted-by":"publisher","first-page":"H2356","DOI":"10.1152\/ajpheart.01310.2006","article-title":"Targeted gene transfer increases contractility and decreases oxygen cost of contractility in normal rat hearts","volume":"292","author":"Sakata","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021113011041495900_B10","first-page":"976","article-title":"Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents","volume":"119","author":"Wu","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2021113011041495900_B11","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nature13073","article-title":"Inhibition of miR-25 improves cardiac contractility in the failing heart","volume":"508","author":"Wahlquist","year":"2014","journal-title":"Nature"},{"key":"2021113011041495900_B12","doi-asserted-by":"publisher","first-page":"5385","DOI":"10.1111\/febs.12193","article-title":"The plasma membrane calcium pump in health and disease","volume":"280","author":"Brini","year":"2013","journal-title":"FEBS J."},{"key":"2021113011041495900_B13","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1152\/physrev.2001.81.1.21","article-title":"Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps","volume":"81","author":"Strehler","year":"2001","journal-title":"Physiol. Rev."},{"key":"2021113011041495900_B14","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1161\/01.RES.0000092142.19896.D9","article-title":"Plasma membrane calcium ATPase overexpression in arterial smooth muscle increases vasomotor responsiveness and blood pressure","volume":"93","author":"Gros","year":"2003","journal-title":"Circ. Res."},{"key":"2021113011041495900_B15","doi-asserted-by":"publisher","first-page":"41246","DOI":"10.1074\/jbc.M307606200","article-title":"Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump","volume":"278","author":"Schuh","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021113011041495900_B16","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1161\/01.RES.83.9.877","article-title":"Overexpression of the sarcolemmal calcium pump in the myocardium of transgenic rats","volume":"83","author":"Hammes","year":"1998","journal-title":"Circ. Res."},{"key":"2021113011041495900_B17","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1161\/CIRCULATIONAHA.106.643791","article-title":"Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b","volume":"115","author":"Oceandy","year":"2007","journal-title":"Circulation"},{"key":"2021113011041495900_B18","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1161\/01.RES.79.4.691","article-title":"Conditional transgene expression in the heart","volume":"79","author":"Yu","year":"1996","journal-title":"Circ. Res."},{"key":"2021113011041495900_B19","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1161\/01.RES.0000056758.73215.5A","article-title":"Conditional expression of a dominant-negative c-Myb in vascular smooth muscle cells inhibits arterial remodeling after injury","volume":"92","author":"You","year":"2003","journal-title":"Circ. Res."},{"key":"2021113011041495900_B20","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1161\/01.CIR.0000105701.98663.D4","article-title":"Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice","volume":"109","author":"Yang","year":"2004","journal-title":"Circulation"},{"key":"2021113011041495900_B21","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1042\/bj3160353","article-title":"Detection of isoform 4 of the plasma membrane calcium pump in human tissues by using isoform-specific monoclonal antibodies","volume":"316","author":"Caride","year":"1996","journal-title":"Biochem. J."},{"key":"2021113011041495900_B22","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S0021-9258(19)70149-5","article-title":"Purified (Ca2+-Mg2+)-ATPase of the erythrocyte membrane. Reconstitution and effect of calmodulin and phospholipids","volume":"256","author":"Niggli","year":"1981","journal-title":"J. Biol. Chem."},{"key":"2021113011041495900_B23","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1111\/j.1469-7793.1997.271be.x","article-title":"Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle","volume":"504","author":"Wickenden","year":"1997","journal-title":"J. Physiol."},{"key":"2021113011041495900_B24","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1006\/jmcc.1999.1018","article-title":"Decreased myocardial nNOS, increased iNOS and abnormal ECGs in mouse models of Duchenne muscular dystrophy","volume":"31","author":"Bia","year":"1999","journal-title":"J. Mol. Cell Cardiol."},{"key":"2021113011041495900_B25","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1093\/hmg\/ddh014","article-title":"Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity","volume":"13","author":"Ohsawa","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2021113011041495900_B26","doi-asserted-by":"publisher","first-page":"975","DOI":"10.2337\/db08-1193","article-title":"GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice","volume":"58","author":"Noyan-Ashraf","year":"2009","journal-title":"Diabetes"},{"key":"2021113011041495900_B27","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1210\/en.2003-0007","article-title":"Cardiac function in mice lacking the glucagon-like peptide-1 receptor","volume":"144","author":"Gros","year":"2003","journal-title":"Endocrinology"},{"key":"2021113011041495900_B28","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1136\/hrt.82.2.192","article-title":"Echocardiographic assessment of ejection fraction in left ventricular hypertrophy","volume":"82","author":"Wandt","year":"1999","journal-title":"Heart"},{"key":"2021113011041495900_B29","doi-asserted-by":"publisher","first-page":"H2054","DOI":"10.1152\/ajpheart.00836.2009","article-title":"Refined approach for quantification of in vivo ischemia-reperfusion injury in the mouse heart","volume":"297","author":"Bohl","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021113011041495900_B30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/S0092-8674(02)00834-6","article-title":"Converging pathways and principles in heart development and disease: CV@CSH","volume":"110","author":"Chien","year":"2002","journal-title":"Cell"},{"key":"2021113011041495900_B31","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1186\/1471-2164-13-552","article-title":"MicroRNAs and cardiac sarcoplasmic reticulum calcium ATPase-2 in human myocardial infarction: expression and bioinformatic analysis","volume":"13","author":"Bostjancic","year":"2012","journal-title":"BMC Genomics"},{"key":"2021113011041495900_B32","doi-asserted-by":"publisher","first-page":"e0122509","DOI":"10.1371\/journal.pone.0122509","article-title":"miR-185 plays an anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways","volume":"10","author":"Kim","year":"2015","journal-title":"PLoS One"},{"key":"2021113011041495900_B33","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1016\/S0002-9440(10)64929-2","article-title":"Doxycycline modulates smooth muscle cell growth, migration, and matrix remodeling after arterial injury","volume":"160","author":"Bendeck","year":"2002","journal-title":"Am. J. Pathol."},{"key":"2021113011041495900_B34","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.yjmcc.2009.11.015","article-title":"Cyclic GMP\/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation. Novel mechanism of cardiac stress modulation by PDE5 inhibition","volume":"48","author":"Koitabashi","year":"2010","journal-title":"J. Mol. Cell Cardiol."},{"key":"2021113011041495900_B35","doi-asserted-by":"publisher","first-page":"41520","DOI":"10.1074\/jbc.M111.290411","article-title":"Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain","volume":"286","author":"Mohamed","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021113011041495900_B36","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1111\/j.1749-6632.1995.tb17414.x","article-title":"Signaling pathways for cardiac growth and hypertrophy. Recent advances and prospects for growth factor therapy","volume":"752","author":"Lembo","year":"1995","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"2021113011041495900_B37","doi-asserted-by":"publisher","first-page":"30816","DOI":"10.1074\/jbc.271.48.30816","article-title":"Expression of the plasma membrane Ca2+-ATPase in myogenic cells","volume":"271","author":"Hammes","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021113011041495900_B38","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1517\/14712590903321462","article-title":"Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure","volume":"10","author":"Lipskaia","year":"2010","journal-title":"Expert. Opin. Biol. Ther."},{"key":"2021113011041495900_B39","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.jjcc.2015.02.006","article-title":"Gene therapy for heart failure","volume":"66","author":"Greenberg","year":"2015","journal-title":"J. Cardiol."},{"key":"2021113011041495900_B40","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1016\/S0140-6736(16)00082-9","article-title":"Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial","volume":"387","author":"Greenberg","year":"2016","journal-title":"Lancet"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/132\/6\/641\/446435\/cs-2017-1337.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/132\/6\/641\/446435\/cs-2017-1337.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T11:58:33Z","timestamp":1638273513000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/132\/6\/641\/72138\/Cardiac-specific-inducible-overexpression-of-human"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,26]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,3,30]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20171337","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,26]]}}}