Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA.
Department of Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25755, USA.
Int J Mol Sci. 2021 Mar 27;22(7):3462. doi: 10.3390/ijms22073462.
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 α1α2 mouse failed to do so in the α1α2. 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.
钠钾-ATP 酶是强心甾（CTS）如哇巴因和地高辛的特定受体。在治疗心脏疾病时使用的药理学浓度下，CTS 抑制钠钾-ATP 酶的离子泵功能。在低得多的浓度下，即在血液中报告的内源性 CTS 浓度范围内，它们通过启动钠钾-ATP 酶介导和活性氧（ROS）依赖性信号来刺激培养的心肌细胞的肥大生长。为了研究内源性 CTS 浓度对体内心脏结构和功能的可能影响，我们比较了表达天然抗性钠钾-ATP 酶α1 的小鼠和基因工程表达对 CTS 具有高亲和力的突变型钠钾-ATP 酶α1 的年龄匹配的小鼠。在该模型中，总心脏钠钾-ATP 酶活性、α1、α2 和β1 蛋白含量保持不变，哇巴因对钠钾-ATP 酶的心脏剂量反应曲线如预期那样向左移位。在 3-6 月龄雄性中，CTS 对α1 敏感性增加导致心脏羰基化蛋白含量显著增加，表明 ROS 产生增加。约 15%的心脏重量-胫骨长度比的适度但显著增加伴随着心肌横截面积的增加被检测到。超声心动图分析未显示任何心脏功能变化，也没有纤维化或胎儿基因程序的再表达。RNA 测序分析表明，与能量代谢相关的途径上调，而与细胞外基质组织相关的途径下调。与后者的功能作用一致，血管紧张素-II 挑战在α1α2 小鼠中引发纤维化，但在α1α2 小鼠中没有引发纤维化。总之，这些结果表明在基线实验室条件下，循环 CTS、钠钾-ATP 酶α1、ROS 和生理性心脏肥大之间存在联系。
