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Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1 s/s α2 s/s Mouse Model of High Affinity for Cardiotonic Steroids.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Mar 27; Vol. 22 (7). Date of Electronic Publication: 2021 Mar 27. - Publication Year :
- 2021
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Abstract
- 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 <superscript>r/r</superscript> α2 <superscript>s/s</superscript> mouse failed to do so in the α1 <superscript>s/s</superscript> α2 <superscript>s/s</superscript> . 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.
- Subjects :
- Angiotensin II pharmacology
Animals
Cardiomegaly pathology
Disease Models, Animal
Echocardiography
Heart drug effects
Male
Mice
Mutation
Ouabain pharmacology
Protein Isoforms
RNA-Seq
Reactive Oxygen Species
Signal Transduction drug effects
Cardiac Glycosides chemistry
Heart physiology
Myocardium enzymology
Sodium-Potassium-Exchanging ATPase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33801629
- Full Text :
- https://doi.org/10.3390/ijms22073462