Upregulation of Piezo1 (Piezo Type Mechanosensitive Ion Channel Component 1) Enhances the Intracellular Free Calcium in Pulmonary Arterial Smooth Muscle Cells From Idiopathic Pulmonary Arterial Hypertension Patients
Upregulation of Piezo1 (Piezo Type Mechanosensitive Ion Channel Component 1) Enhances the Intracellular Free Calcium in Pulmonary Arterial Smooth Muscle Cells From Idiopathic Pulmonary Arterial Hypertension Patients
复制标题
Piezo1（压电型机械敏感离子通道成分 1）的上调可增强特发性肺动脉高压患者肺动脉平滑肌细胞中的细胞内游离钙。
DOI：
10.1161/hypertensionaha.120.16629
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发表时间：
2021-06-01
期刊：
影响因子：
8.3
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Liao, Jing;Lu, Wenju;Wang, Jian
文本中提供了补充数字内容。新兴研究报道了机械敏感性 Piezo1（压电型机械敏感性离子通道成分 1）通过细胞内钙稳态的机械作用在调节血管张力方面发挥着重要作用。然而，Piezo1 在肺血管中的具体作用仍不完全清楚。我们的目的是研究 Piezo1 在正常和肺动脉高压 (PAH) 条件下是否以及如何调节人肺动脉平滑肌细胞 (PASMC) 的细胞内钙稳态。从对照供体和特发性 PAH 患者中分离培养的人 PASMC 用作细胞模型。进行基于 Fura-2 的细胞内钙成像来测量细胞内游离钙浓度 ([Ca2+]i)。结果表明，Yoda1 激活 Piezo1，通过位于亚细胞器（包括内质网/肌浆网、线粒体和细胞核）的细胞内（内）Piezo1 诱导细胞内钙从内部钙库释放，从而增加 [Ca2+]i；以及细胞外钙通过质膜定位的 Piezo1 流入，其机制与钙库操作无关。此外，Piezo1 介导的 [Ca2+]i 增加与 PASMC 的收缩和增殖增加有关。 Yoda1 在内皮剥脱的大鼠肺内动脉中诱导剂量依赖性血管收缩。与供体 PASMC 相比，在特发性 PAH-PASMC 中观察到 Piezo1 的显着上调和活性增加，导致特发性 PAH-PASMC 的 [Ca2+]i 增加和过度增殖。总之，Piezo1 通过触发细胞内钙释放和细胞外流入来介导 [Ca2+]i 的增加。 Piezo1 表达和活性的增强至少部分解释了特发性 PAH-PASMC 中 [Ca2+]i 的异常升高和增殖。
Supplemental Digital Content is available in the text. Emerging studies have reported the mechanosensitive Piezo1 (piezo type mechanosensitive ion channel component 1) plays essential roles in regulating the vascular tone through mechanistic actions on intracellular calcium homeostasis. However, the specific roles of Piezo1 in pulmonary vessels remain incompletely understood. We aim to investigate whether and how Piezo1 regulates the intracellular calcium homeostasis in human pulmonary arterial smooth muscle cells (PASMCs) under normal and pulmonary arterial hypertension (PAH) conditions. Cultured human PASMCs isolated from both control donors and idiopathic PAH patients were used as cell models. Fura-2 based intracellular calcium imaging was performed to measure the intracellular free calcium concentration ([Ca2+]i). Results showed that activation of Piezo1 by Yoda1 increases [Ca2+]i by inducing both intracellular calcium release from internal calcium stores through the intracellular (intra-) Piezo1 localized at the subcellular organelles, including endoplasmic reticulum/sarcoplasmic reticulum, mitochondria, and nucleus; as well as extracellular calcium influx through the plasma membrane-localized Piezo1 in a mechanism independent of the store-operated calcium entry. Moreover, the Piezo1-mediated increase of [Ca2+]i is linked to increased contraction and proliferation of PASMCs. Yoda1 induces dose-dependent vasocontraction in endothelium-denuded rat intrapulmonary arteries. Significant upregulation and increased activity of Piezo1 were observed in idiopathic PAH-PASMCs versus donor-PASMCs, contributing to the increased [Ca2+]i and excessive proliferation of idiopathic PAH-PASMCs. In summary, Piezo1 mediates the increase of [Ca2+]i by triggering both intracellular calcium release and extracellular influx. The enhanced Piezo1 expression and activity accounts, at least partially, for the abnormally elevated [Ca2+]i and proliferation in idiopathic PAH-PASMCs.