{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:30:04Z","timestamp":1779913804218,"version":"3.53.1"},"reference-count":103,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,27]],"date-time":"2021-03-27T00:00:00Z","timestamp":1616803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["AHA19AIREA34450278"],"award-info":[{"award-number":["AHA19AIREA34450278"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["AHA-UGR 18UFEL33960330"],"award-info":[{"award-number":["AHA-UGR 18UFEL33960330"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R15HL145666"],"award-info":[{"award-number":["R15HL145666"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Na\/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na\/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na\/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na\/K-ATPase \u03b11 and age-matched mice genetically engineered to express a mutated Na\/K-ATPase \u03b11 with high affinity for CTS. In this model, total cardiac Na\/K-ATPase activity, \u03b11, \u03b12, and \u03b21 protein content remained unchanged, and the cardiac Na\/K-ATPase dose\u2013response curve to ouabain shifted to the left as expected. In males aged 3\u20136 months, increased \u03b11 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the \u03b11r\/r\u03b12s\/s mouse failed to do so in the \u03b11s\/s\u03b12s\/s. Taken together, these results are indicative of a link between circulating CTS, Na\/K-ATPase \u03b11, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.<\/jats:p>","DOI":"10.3390\/ijms22073462","type":"journal-article","created":{"date-parts":[[2021,3,28]],"date-time":"2021-03-28T22:09:01Z","timestamp":1616969341000},"page":"3462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na\/K-ATPase \u03b11s\/s\u03b12s\/s Mouse Model of High Affinity for Cardiotonic Steroids"],"prefix":"10.3390","volume":"22","author":[{"given":"Pauline V.","family":"Marck","sequence":"first","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-1732","authenticated-orcid":false,"given":"Marco T.","family":"Pessoa","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhui","family":"Xu","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-6441","authenticated-orcid":false,"given":"Laura C.","family":"Kutz","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9557-5352","authenticated-orcid":false,"given":"Dominic M.","family":"Collins","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6549-3393","authenticated-orcid":false,"given":"Yanling","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25755, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cierra","family":"King","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6204-3028","authenticated-orcid":false,"given":"Qiming","family":"Duan","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9192-2673","authenticated-orcid":false,"given":"Liquan","family":"Cai","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey X.","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry B.","family":"Lingrel","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Xie","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0812-8135","authenticated-orcid":false,"given":"Jiang","family":"Tian","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine V.","family":"Pierre","sequence":"additional","affiliation":[{"name":"Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1161\/01.HYP.0000165024.47728.f7","article-title":"Ouabain-like compound changes rapidly on physical exercise in humans and dogs: Effects of beta-blockade and angiotensin-converting enzyme inhibition","volume":"45","author":"Bauer","year":"2005","journal-title":"Hypertension"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1124\/pr.108.000711","article-title":"Endogenous cardiotonic steroids: Physiology, pharmacology, and novel therapeutic targets","volume":"61","author":"Bagrov","year":"2009","journal-title":"Pharmacol. 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