Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Department of Psychiatry, Taipei Medical University Hospital, Taipei 11031, Taiwan.
Int J Mol Sci. 2021 Jan 15;22(2):842. doi: 10.3390/ijms22020842.
Cardiac fibrosis plays a vital role in the pathogenesis of heart failure. Fibroblast activity is enhanced by increases in store-operated Ca entry (SOCE) and calcium release-activated calcium channel protein 1 (Orai1) levels. Lithium regulates SOCE; however, whether therapeutic concentrations of lithium can be used to inhibit cardiac fibrogenesis is unknown. Migration and proliferation assays, Western blotting, real-time reverse-transcription polymerase chain reaction analysis, and calcium fluorescence imaging were performed in human cardiac fibroblasts treated with or without LiCl at 1.0 mM (i.e., therapeutic peak level) or 0.1 mM (i.e., therapeutic trough level) for 24 h. Results showed that LiCl (0.1 mM, but not 1.0 mM) inhibited the migration and collagen synthesis ability of cardiac fibroblasts. Additionally, thapsigargin-induced SOCE was reduced in fibroblasts treated with LiCl (0.1 mM). The expression level of Orai1 was lower in LiCl (0.1 mM)-treated fibroblasts relative to the fibroblasts without LiCl treatment. Fibroblasts treated with a combination of LiCl (0.1 mM) and 2-APB (10 μM, an Orai1 inhibitor) demonstrated similar migration and collagen synthesis abilities as those in LiCl (0.1 mM)-treated fibroblasts. Altogether, lithium at therapeutic trough levels reduced the migration and collagen synthesis abilities of human cardiac fibroblasts by inhibiting SOCE and Orai1 expression.
心肌纤维化在心力衰竭的发病机制中起着至关重要的作用。成纤维细胞活性通过增加储存操作钙内流（SOCE）和钙释放激活钙通道蛋白 1（Orai1）水平而增强。锂可调节 SOCE；然而，治疗浓度的锂是否可用于抑制心肌纤维化尚不清楚。用 1.0 mM（即治疗峰值水平）或 0.1 mM（即治疗谷值水平）的 LiCl 处理人心脏成纤维细胞 24 小时后，进行迁移和增殖测定、Western blot 分析、实时逆转录聚合酶链反应分析和钙荧光成像。结果表明，LiCl（0.1 mM，但不是 1.0 mM）抑制了心肌成纤维细胞的迁移和胶原合成能力。此外，用 LiCl（0.1 mM）处理的成纤维细胞中，钙网织蛋白诱导的 SOCE 减少。与未用 LiCl 处理的成纤维细胞相比，LiCl（0.1 mM）处理的成纤维细胞中 Orai1 的表达水平较低。用 LiCl（0.1 mM）和 2-APB（10 μM，Orai1 抑制剂）联合处理的成纤维细胞表现出与 LiCl（0.1 mM）处理的成纤维细胞相似的迁移和胶原合成能力。总之，治疗谷值水平的锂通过抑制 SOCE 和 Orai1 表达来降低人心脏成纤维细胞的迁移和胶原合成能力。
