{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:22:59Z","timestamp":1792736579117,"version":"4.5.0"},"reference-count":40,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2013,2,1]]},"abstract":"<jats:p>Previous studies have shown that digitalis drugs, acting as specific inhibitors of cardiac Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>-ATPase, not only cause positive inotropic effects, but also activate cell signaling pathways that lead to cardiac myocyte hypertrophy. A major aim of this work was to assess the role of Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup>-exchanger, NCX1, in the above two seemingly related drug effects. Using a mouse with ventricular-specific knockout (KO) of NCX1, ouabain-induced positive inotropy that was evident in isolated wild-type (Wt) hearts was clearly reduced in KO hearts. Ouabain also increased Ca<jats:sup>2+<\/jats:sup>transient amplitudes in Wt myocytes, but not in KO myocytes. Ouabain-induced activations of ERK 1\/2 were noted in Wt myocytes, but not in KO myocytes; however, ouabain activated PI3K1A and Akt in both Wt and KO myocytes. Protein synthesis rate, as a measure of hypertrophy, was increased by ouabain in Wt and KO myocytes; these drug effects were prevented by a PI3K inhibitor but not by a MEK\/ERK inhibitor. Hypertrophy caused by ET-1, but not that induced by ouabain, was accompanied by upregulation of BNP gene in Wt and KO myocytes. The findings indicate 1) the necessity of NCX1 for positive inotropic action of ouabain; 2) the irrelevance of NCX1 and ERK 1\/2 activation to ouabain-induced hypertrophy; and 3) that hypertrophy caused by ouabain through the activation of PI3K1A\/Akt pathway is likely to be beneficial to the heart.<\/jats:p>","DOI":"10.1152\/ajpheart.00462.2012","type":"journal-article","created":{"date-parts":[[2012,12,2]],"date-time":"2012-12-02T01:45:02Z","timestamp":1354412702000},"page":"H427-H435","source":"Crossref","is-referenced-by-count":34,"title":["Different roles of the cardiac Na<sup>+<\/sup>\/Ca<sup>2+<\/sup>-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy"],"prefix":"10.1152","volume":"304","author":[{"given":"Yan","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cancer Biology,"},{"name":"Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric E.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Giovannucci","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine V.","family":"Pierre","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cancer Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D.","family":"Philipson","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Askari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cancer Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cancer Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.111252"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2010.04.005"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfp094"},{"key":"B4","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/S0022-3565(25)09003-2","volume":"62","author":"Cattell M","year":"1938","journal-title":"J Pharmacol Exp Ther"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00159.2005"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.595231"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs213"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1998.274.5.C1226"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1940.00190080045003"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000142316.08250.68"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000187456.06162.cb"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.71.102201.141218"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05088.x"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00466-2"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.24.15249"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2828(70)90029-5"},{"key":"B17","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0031-6997(25)06889-9","volume":"23","author":"Lee KS","year":"1971","journal-title":"Pharmacol Rev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.201988"},{"key":"B19","doi-asserted-by":"crossref","first-page":"27838","DOI":"10.1074\/jbc.M002950200","volume":"275","author":"Liu J","year":"2000","journal-title":"J Biol Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00555.2002"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00158.2007"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.21.9491-9502.2005"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.64.3.542"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107892200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-200304000-00014"},{"key":"B26","first-page":"271","volume":"357","author":"O'Connell TD","year":"2007","journal-title":"Methods Mol Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.17.10372"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.003"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000196563.84231.21"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.091538"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/hh0302.104562"},{"key":"B32","first-page":"321","volume":"268","author":"Schwartz A","year":"1988","journal-title":"Prog Clin Biol Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/BF00229801"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(57)90343-8"},{"key":"B35","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF00768846","volume":"24","author":"Skou JC","year":"1992","journal-title":"J Bioenerg Biomembr"},{"key":"B36","first-page":"358","volume":"38","author":"Smith TW","year":"1988","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1681.2003.03925.x"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.71.1.9"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00043.2010"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1033.2002.02910.x"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00462.2012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T01:48:17Z","timestamp":1745372897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00462.2012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,1]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,2,1]]}},"alternative-id":["10.1152\/ajpheart.00462.2012"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00462.2012","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,1]]}}}