Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells.
Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells.
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DOI：
10.33594/000000131
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Sathish, Venkatachalem
中科院分区：
文献类型：
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作者：
Kalidhindi, Rama Satyanarayana Raju;Katragadda, Rathnavali;Sathish, Venkatachalem
背景/目标：随着女性哮喘患病率的增加，女性性类固醇的有害作用已被探索，但雄激素的潜在保护作用尚未确定。气道平滑肌（ASM）是哮喘收缩和重塑的关键细胞类型。没有关于人ASM细胞中雄激素受体（AR）的表达和功能的数据。方法：我们使用来自非哮喘患者与哮喘患者的原代人ASM细胞来确定基线时AR的表达，并使用Western印迹/qRT-PCR测量炎症，以及使用Fluo-3加载的真实的时间[Ca 2 +]i成像测量AR在调节细胞内Ca 2+（[Ca 2 +]i）中的作用。我们发现，与女性相比，男性ASM的基线AR更大，并且随着炎症/哮喘的增加而增加。雄激素通过AR减弱了TNF α或IL-13诱导的男性和女性ASM [Ca 2 +]i的增强，在哮喘患者中保持有效性。AR的作用包括通过L型通道减少Ca 2+内流和钙库操作的Ca 2+内流，后者通过下调STIM 1和Orai 1以及增加TMEM 66来实现。结论：女性哮喘患者ASM中AR表达增加，但仍保留了降低[Ca 2 +]i以减轻气道高反应性的功能。
BACKGROUND/AIMS: With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells.METHODS: We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca2+ ([Ca2+]i) measured using Fluo-3 loaded real time [Ca2+]i imaging.RESULTS: We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFalpha or IL-13-induced enhancement of ASM [Ca2+]i in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca2+ influx via L-type channels and store-operated Ca2+ entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66.CONCLUSION: Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca2+]i towards alleviating airway hyperresponsiveness.