Up-regulation of KCa3.1 promotes human airway smooth muscle cell phenotypic modulation.
Up-regulation of KCa3.1 promotes human airway smooth muscle cell phenotypic modulation.
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DOI：
10.1016/j.phrs.2013.09.002
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发表时间：
2013-11
影响因子：
9.3
通讯作者：
Z.-H. Yu;Y-X Wang;Y. Song;H-Z Lu;Lina Hou;Y-Y Cui-Y;H-Z Chen
中科院分区：
文献类型：
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作者：
Z.-H. Yu;Y-X Wang;Y. Song;H-Z Lu;Lina Hou;Y-Y Cui-Y;H-Z Chen
气道平滑肌（ASM）细胞表型调节的特征是收缩表型和增殖表型之间的可逆转换，被认为有助于增殖性疾病，例如过敏性哮喘和慢性阻塞性肺疾病（COPD）。 KCa3.1 已被认为参与调节 ASM 细胞活化、增殖和迁移。然而，关于 KCa3.1 在 ASM 细胞表型调节中的确切作用知之甚少。为了阐明 KCa3.1 在调节 ASM 细胞表型调节中的作用，我们研究了 KCa3.1 通道对原代人支气管平滑肌 (BSM) 细胞的 ASM 收缩标记蛋白表达、增殖和迁移的影响。我们发现PDGF增加了BSM细胞中KCa3.1通道的表达，同时收缩表型标记蛋白的表达显着降低，包括平滑肌肌球蛋白重链（SMMHC）、平滑肌α-肌动蛋白（α-SMA）、心肌素和KCa1.1。 KCa3.1 阻断剂、TRAM-34 或 KCa3.1 基因沉默显着减弱了这些变化。 KCa3.1 的药理学阻断或基因沉默也抑制 PDGF 诱导的人 BSM 细胞迁移和增殖，并伴随膜去极化导致细胞内游离 Ca2+ 水平降低，导致细胞周期蛋白 D1 水平降低和细胞周期停滞在 G0-G1 期。此外，PDGF 诱导的 KCa3.1 上调和 BSM 收缩标记蛋白下调受到 ERK 抑制剂 U0126 和 AKT 抑制剂 LY294002 的调节。这些发现强调了 KCa3.1 通道在人类 BSM 细胞表型调节中的新作用，并为增殖性气道疾病的治疗干预提供了潜在靶点。
Airway smooth muscle (ASM) cell phenotype modulation, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to proliferative diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD). KCa3.1 has been suggested to be involved in regulating ASM cell activation, proliferation, and migration. However, little is known regarding the exact role of KCa3.1 in ASM cell phenotypic modulation. To elucidate the role of KCa3.1 in regulating ASM cell phenotypic modulation, we investigated the effects of KCa3.1 channels on ASM contractile marker protein expression, proliferation and migration of primary human bronchial smooth muscle (BSM) cells. We found that PDGF increased KCa3.1 channel expression in BSM cells with a concomitant marked decrease in the expression of contractile phenotypic marker proteins including smooth muscle myosin heavy chain (SMMHC), smooth muscle α-actin (α-SMA), myocardin and KCa1.1. These changes were significantly attenuated by the KCa3.1 blocker, TRAM-34, or gene silencing of KCa3.1. Pharmacological blockade or gene silencing of KCa3.1 also suppressed PDGF-induced human BSM cell migration and proliferation accompanied by a decrease in intracellular free Ca2+levels as a consequence of membrane depolarization, resulting in a reduction in cyclin D1 level and cell cycle arrest at G0-G1 phase. Additionally, PDGF-induced up-regulation of KCa3.1 and down-regulation of BSM contractile marker proteins were regulated by the ERK inhibitor U0126 and the AKT inhibitor LY294002. These findings highlight a novel role for the KCa3.1 channel in human BSM cell phenotypic modulation and provide a potential target for therapeutic intervention for proliferative airway diseases.