鲁比前列酮通过激活 CFTR 对 iPS 细胞衍生的心肌细胞产生负性变时和变力作用。
Negative chronotropic and inotropic effects of lubiprostone on iPS cell-derived cardiomyocytes via activation of CFTR.
机构信息
Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
Department of Cellular and Integrative Physiology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan.
出版信息
BMC Complement Med Ther. 2020 Apr 19;20(1):118. doi: 10.1186/s12906-020-02923-6.
BACKGROUND
Lubiprostone (LBP) is a novel chloride channel opener that has been reported to activate chloride channel protein 2 (ClC-2) and cystic fibrosis transmembrane conductance regulator (CFTR). LBP facilitates fluid secretion by activating CFTR in the intestine and is used as a drug for treating chronic constipation. While ClC-2 and CFTR expression has been confirmed in cardiomyocytes (CMs), the effect of LBP on CMs has not yet been investigated. Thus, the present study aimed to investigate the effect of LBP on CMs using mouse-induced pluripotent stem (iPS) cell-derived CMs (iPS-CMs).
METHODS
We induced mouse iPS cells into CMs through embryoid body (EB) formation. We compared the differentiated cells to CMs isolated from adult and fetal mice using gene expression, spontaneous beating rate, and contraction ratio analyses.
RESULTS
Gene expression analysis revealed that, in the iPS-CMs, the mRNA expression of the undifferentiated cell markers Rex1 and Nanog decreased, whereas the expression of the unique cardiomyocyte markers cardiac troponin I (cTnI) and cardiac troponin T (cTNT), increased. Immunostaining showed that the localization of cTnI and connexin-43 in the iPS-CMs was similar to that in the primary fetal CMs (FCMs) and adult CMs (ACMs). LBP decreased the spontaneous beating rate of the iPS-CMs and FCMs, and decreased the contraction ratio of the iPS-CMs and ACMs. The reduction in the beating rate and contraction ratio caused by LBP was inhibited by glycine hydrazide (GlyH), which is a CFTR inhibitor.
CONCLUSION
These results suggest that LBP stimulates CFTR in CMs and that LBP has negative chronotropic and inotropic effects on CMs. LBP may be useful for treating cardiac diseases such as heart failure, ischemia, and arrhythmia.
背景
鲁比前列酮（LBP）是一种新型的氯离子通道开放剂，据报道可激活氯离子通道蛋白 2（ClC-2）和囊性纤维化跨膜电导调节因子（CFTR）。LBP 通过激活肠道中的 CFTR 促进液体分泌，被用作治疗慢性便秘的药物。虽然 ClC-2 和 CFTR 在心肌细胞（CMs）中已有表达的证实，但 LBP 对 CMs 的影响尚未得到研究。因此，本研究旨在使用小鼠诱导多能干细胞（iPS）细胞衍生的 CMs（iPS-CMs）来研究 LBP 对 CMs 的影响。
方法
我们通过胚状体（EB）形成将小鼠 iPS 细胞诱导分化为 CMs。我们通过基因表达、自发搏动率和收缩比分析，将分化细胞与来自成年和胎儿小鼠的 CMs 进行比较。
结果
基因表达分析显示，在 iPS-CMs 中，未分化细胞标志物 Rex1 和 Nanog 的 mRNA 表达减少，而独特的心肌细胞标志物肌钙蛋白 I（cTnI）和肌钙蛋白 T（cTNT）的表达增加。免疫染色显示，iPS-CMs 中的 cTnI 和连接蛋白-43 的定位与原代胎儿 CMs（FCMs）和成年 CMs（ACMs）相似。LBP 降低了 iPS-CMs 和 FCMs 的自发搏动率，并降低了 iPS-CMs 和 ACMs 的收缩比。LBP 引起的搏动率和收缩比的降低被 CFTR 抑制剂甘氨酰肼（GlyH）抑制。
结论
这些结果表明，LBP 刺激 CMs 中的 CFTR，并且 LBP 对 CMs 具有负性变力和变时作用。LBP 可能对治疗心力衰竭、缺血和心律失常等心脏疾病有用。
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