Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids
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 en...
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| Format: | Article |
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/7/3462 |
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| author | Pauline V. Marck Marco T. Pessoa Yunhui Xu Laura C. Kutz Dominic M. Collins Yanling Yan Cierra King Xiaoliang Wang Qiming Duan Liquan Cai Jeffrey X. Xie Jerry B. Lingrel Zijian Xie Jiang Tian Sandrine V. Pierre |
| author_facet | Pauline V. Marck Marco T. Pessoa Yunhui Xu Laura C. Kutz Dominic M. Collins Yanling Yan Cierra King Xiaoliang Wang Qiming Duan Liquan Cai Jeffrey X. Xie Jerry B. Lingrel Zijian Xie Jiang Tian Sandrine V. Pierre |
| author_sort | Pauline V. Marck |
| collection | DOAJ |
| description | 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 α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 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 α1<sup>r/r</sup>α2<sup>s/s</sup> mouse failed to do so in the α1<sup>s/s</sup>α2<sup>s/s</sup>. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions. |
| first_indexed | 2024-03-10T12:51:47Z |
| format | Article |
| id | doaj.art-eb7f62c3bf0446d2814a98a8a367e678 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:51:47Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-eb7f62c3bf0446d2814a98a8a367e6782023-11-21T13:03:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01227346210.3390/ijms22073462Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic SteroidsPauline V. Marck0Marco T. Pessoa1Yunhui Xu2Laura C. Kutz3Dominic M. Collins4Yanling Yan5Cierra King6Xiaoliang Wang7Qiming Duan8Liquan Cai9Jeffrey X. Xie10Jerry B. Lingrel11Zijian Xie12Jiang Tian13Sandrine V. Pierre14Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USADepartment of Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25755, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USADepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USADepartment of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAMarshall Institute for Interdisciplinary Research, Huntington, WV 25703, USAThe 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 α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 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 α1<sup>r/r</sup>α2<sup>s/s</sup> mouse failed to do so in the α1<sup>s/s</sup>α2<sup>s/s</sup>. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.https://www.mdpi.com/1422-0067/22/7/3462Na/K-ATPasecardiotonic steroidsisoformreactive oxygen specieshypertrophy |
| spellingShingle | Pauline V. Marck Marco T. Pessoa Yunhui Xu Laura C. Kutz Dominic M. Collins Yanling Yan Cierra King Xiaoliang Wang Qiming Duan Liquan Cai Jeffrey X. Xie Jerry B. Lingrel Zijian Xie Jiang Tian Sandrine V. Pierre Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids International Journal of Molecular Sciences Na/K-ATPase cardiotonic steroids isoform reactive oxygen species hypertrophy |
| title | Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids |
| title_full | Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids |
| title_fullStr | Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids |
| title_full_unstemmed | Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids |
| title_short | Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1<sup>s/s</sup>α2<sup>s/s</sup> Mouse Model of High Affinity for Cardiotonic Steroids |
| title_sort | cardiac oxidative signaling and physiological hypertrophy in the na k atpase α1 sup s s sup α2 sup s s sup mouse model of high affinity for cardiotonic steroids |
| topic | Na/K-ATPase cardiotonic steroids isoform reactive oxygen species hypertrophy |
| url | https://www.mdpi.com/1422-0067/22/7/3462 |
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