Katoh Daisuke, Hongo Kenichi, Ito Keiichi, Yoshino Takuya, Kayama Yosuke, Kawai Makoto, Date Taro, Yoshimura Michihiro
Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
Int J Cardiol Heart Vessel. 2014 Mar 13;3:49-56. doi: 10.1016/j.ijchv.2014.03.001. eCollection 2014 Jun.
Glucocorticoids as well as mineralocorticoid have been shown to play essential roles in the regulation of electrical and mechanical activities in cardiomyocytes. Excess of these hormones is an independent risk factor for cardiovascular disease. Intracellular sodium ([Na]) kinetics are involved in cardiac diseases, including ischemia, heart failure and hypertrophy. However, intrinsic mediators that regulate [Na] in cardiomyocytes have not been widely discussed. Moreover, the quantitative estimation of altered [Na] in cultured cardiomyocytes and the association between the level of [Na] and the severity of pathological conditions, such as hypertrophy, have not been precisely reported.
We herein demonstrate the quantitative estimation of [Na] in cultured neonatal rat cardiomyocytes following 24 h of treatment with corticosterone, aldosterone and dexamethasone. The physiological concentration of glucocorticoids increased [Na] up to approximately 2.5 mM (an almost 1.5-fold increase compared to the control) in a dose-dependent manner; this effect was blocked by a glucocorticoid receptor (GR) antagonist but not a mineralocorticoid receptor antagonist. Furthermore, glucocorticoids induced cardiac hypertrophy, and the hypertrophic gene expression was positively and significantly correlated with the level of [Na]. Dexamethasone induced the upregulation of Na/Ca exchanger 1 at the mRNA and protein levels.
The physiological concentration of glucocorticoids increases [Na] via GR. The dexamethasone-induced upregulation of NCX1 is partly involved in the glucocorticoid-induced alteration of [Na] in cardiomyocytes. These results provide new insight into the mechanisms by which glucocorticoid excess within a physiological concentration contributes to the development of cardiac pathology.
糖皮质激素以及盐皮质激素已被证明在心肌细胞电活动和机械活动的调节中发挥重要作用。这些激素过量是心血管疾病的独立危险因素。细胞内钠（[Na]）动力学参与包括缺血、心力衰竭和肥大在内的心脏疾病。然而，调节心肌细胞中[Na]的内在介质尚未得到广泛讨论。此外，培养的心肌细胞中[Na]改变的定量估计以及[Na]水平与肥大等病理状况严重程度之间的关联尚未得到精确报道。
我们在此展示了用皮质酮、醛固酮和地塞米松处理24小时后培养的新生大鼠心肌细胞中[Na]的定量估计。糖皮质激素的生理浓度以剂量依赖方式使[Na]增加至约2.5 mM（与对照相比几乎增加了1.5倍）；这种作用被糖皮质激素受体（GR）拮抗剂阻断，但未被盐皮质激素受体拮抗剂阻断。此外，糖皮质激素诱导心脏肥大，且肥大基因表达与[Na]水平呈正相关且显著相关。地塞米松在mRNA和蛋白质水平诱导钠/钙交换体1上调。
糖皮质激素的生理浓度通过GR增加[Na]。地塞米松诱导的NCX1上调部分参与了糖皮质激素诱导的心肌细胞中[Na]的改变。这些结果为生理浓度内糖皮质激素过量导致心脏病理发展的机制提供了新的见解。
