Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Sci Rep. 2018 Feb 26;8(1):3624. doi: 10.1038/s41598-018-21812-0.
The aims of the present study were to examine signaling mechanisms underlying transforming growth factor β1 (TGF-β1)-induced airway smooth muscle cells (ASMCs) proliferation and to determine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on TGF-β1-induced ASMCs proliferation and its potential mechanisms. TGF-β1 reduced microRNA-206 (miR-206) level by activating Smad2/3, and this in turn up-regulated histone deacetylase 4 (HDAC4) and consequently increased cyclin D1 protein leading to ASMCs proliferation. Prior incubation of ASMCs with metformin induced AMPK activation and blocked TGF-β1-induced cell proliferation. Activation of AMPK slightly attenuated TGF-β1-induced miR-206 suppression, but dramatically suppressed TGF-β1-caused HDAC4 up-expression and significantly increased HDAC4 phosphorylation finally leading to reduction of up-regulated cyclin D1 protein expression. Our study suggests that activation of AMPK modulates miR-206/HDAC4/cyclin D1 signaling pathway, particularly targeting on HDAC4, to suppress ASMCs proliferation and therefore has a potential value in the prevention and treatment of asthma by alleviating airway remodeling.
本研究旨在探讨转化生长因子β1（TGF-β1）诱导的气道平滑肌细胞（ASMCs）增殖的信号转导机制，并确定腺苷单磷酸激活蛋白激酶（AMPK）的激活对 TGF-β1 诱导的 ASMCs 增殖及其潜在机制的影响。TGF-β1 通过激活 Smad2/3 降低 microRNA-206（miR-206）水平，进而上调组蛋白去乙酰化酶 4（HDAC4），从而增加细胞周期蛋白 D1 蛋白，导致 ASMCs 增殖。ASMCs 先用二甲双胍孵育可诱导 AMPK 激活并阻断 TGF-β1 诱导的细胞增殖。AMPK 的激活轻微减弱了 TGF-β1 诱导的 miR-206 抑制，但显著抑制了 TGF-β1 引起的 HDAC4 上调表达，并显著增加了 HDAC4 磷酸化，最终导致上调的细胞周期蛋白 D1 蛋白表达减少。我们的研究表明，AMPK 的激活调节了 miR-206/HDAC4/细胞周期蛋白 D1 信号通路，特别是针对 HDAC4，从而抑制 ASMCs 的增殖，因此在通过减轻气道重塑预防和治疗哮喘方面具有潜在价值。
