GSE169734
Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase a1s/sa2s/s 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 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 a1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase a1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, a1, a2 and ß1 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 a1 sensitivity to CTS resulted in a significant increase of 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 of 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 a1r/ra2s/s mouse failed to do so in the a1s/sa2s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase a1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions. Overall design: Whole heart mRNA from 3-month old Na/K-ATPase a1r/ra2s/s (resistant) and Na/K-ATPase a1s/sa2s/s (sensitive) mice.