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PTEN 通过调节 CD38/Ca/CREB 信号通路参与哮喘的气道重塑。

PTEN participates in airway remodeling of asthma by regulating CD38/Ca/CREB signaling.

机构信息

Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710004, Shaanxi Province, PR China.

出版信息

Aging (Albany NY). 2020 Aug 27;12(16):16326-16340. doi: 10.18632/aging.103664.

DOI:10.18632/aging.103664
PMID:32889801
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7485701/
Abstract

Both phosphatase and tensin homologue deleted on chromosome ten (PTEN) and cluster of differentiation 38 (CD38) have been suggested to be key regulators of the pathogenesis of asthma. However, the precise role and molecular mechanisms by which PTEN and CD38 are involved in airway remodeling throughout asthma pathogenesis remains poorly understood. This study aimed to elucidate the role of PTEN and CD38 in airway remodeling of asthma. Exposure to tumor necrosis factor-α (TNF-α) in airway smooth muscle (ASM) cells markedly decreased PTEN expression, and increased expression of CD38. Overexpression of PTEN suppressed the expression of CD38 and downregulated proliferation and migration induced by TNF-α stimulation, which was partially reversed by CD38 overexpression. PTEN/CD38 axis regulated Ca2+ levels and cyclic AMP response-element binding protein (CREB) phosphorylation in TNF-α-stimulated ASM cells. The in vitro knockdown of CD38 or overexpression of PTEN remarkably restricted airway remodeling and decreased Ca2+ concentrations and CREB phosphorylation in asthmatic mice. CD38 overexpression abolished the inhibitory effects of PTEN overexpression on airway remodeling. These findings demonstrate that PTEN inhibits airway remodeling of asthma through the downregulation of CD38-mediated Ca2+/CREB signaling, highlighting a key role of PTEN/CD38/Ca2+/CREB signaling in the molecular pathogenesis of asthma.

摘要

磷酸酶和张力蛋白同源物缺失于第十号染色体（PTEN）和分化群 38（CD38）已被认为是哮喘发病机制的关键调节因子。然而，PTEN 和 CD38 通过何种确切的作用和分子机制参与哮喘发病过程中的气道重塑仍知之甚少。本研究旨在阐明 PTEN 和 CD38 在哮喘气道重塑中的作用。肿瘤坏死因子-α（TNF-α）在气道平滑肌（ASM）细胞中的暴露显著降低了 PTEN 的表达，增加了 CD38 的表达。PTEN 的过表达抑制了 CD38 的表达，并下调了 TNF-α刺激诱导的增殖和迁移，而过表达 CD38 部分逆转了这一作用。PTEN/CD38 轴调节 TNF-α刺激的 ASM 细胞中的 Ca2+水平和环磷酸腺苷反应元件结合蛋白（CREB）磷酸化。体外敲低 CD38 或过表达 PTEN 可显著限制哮喘小鼠的气道重塑，并降低 Ca2+浓度和 CREB 磷酸化。CD38 的过表达消除了 PTEN 过表达对气道重塑的抑制作用。这些发现表明，PTEN 通过下调 CD38 介导的 Ca2+/CREB 信号通路抑制哮喘气道重塑，强调了 PTEN/CD38/Ca2+/CREB 信号通路在哮喘发病机制中的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/6c90506b4c2e/aging-12-103664-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/487eb23b95b6/aging-12-103664-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/8731465e5c89/aging-12-103664-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/a92da9bfe615/aging-12-103664-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/126d541841b9/aging-12-103664-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/2bc3029240a0/aging-12-103664-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/4f811132ac50/aging-12-103664-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/31fd33c6511a/aging-12-103664-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/8731465e5c89/aging-12-103664-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6576/7485701/6c90506b4c2e/aging-12-103664-g010.jpg

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