Department of Orthodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, P.R. China.
Department of Orthodontics, Shanghai Stomatological Hospital, Shanghai 200001, P.R. China.
Int J Mol Med. 2017 Nov;40(5):1347-1356. doi: 10.3892/ijmm.2017.3123. Epub 2017 Sep 7.
Deficiency in the functioning of the genioglossus, which is one of the upper airway dilator muscles, is an important cause of obstructive sleep apnea/hypopnea syndrome (OSAHS). Estrogens have been reported to inhibit hypoxia-inducible factor-1α (HIF-1α) expression in hypoxia, regulating its target genes and exerting protective effects on the genioglossus in chronic intermittent hypoxia (CIH). This study aimed to investigate the role of 17β-estradiol (E2) and a resveratrol dimer (RD) on HIF-1α and the underlying mechanism. Mouse genioglossus myoblasts were isolated and cultured, and the estrogen receptor α (ERα) shRNA lentivirus was used for gene knockdown. Then MTT assay was used to determine the effects of E2 and RD on the viability of the cells. Cells in different groups were treated with different agents (E2, or RD, or E2 and SB203580), incubated under normoxia or hypoxia for 24 h, and then expression levels of HIF-1α, ERα, ERβ, total-p38 MAPK and phospho-p38 MAPK were detected. We observed that both E2 and RD inhibited the overexpression of HIF-1α induced by hypoxia at the mRNA and protein levels, and these effects were eliminated by genetic silencing of ERα by RNAi. In addition, we found that E2 activated p38 MAPK pathways to inhibit HIF-1α expression. On the whole, ERα may be responsible for downregulation of HIF-1α by E2 or RD via activation of downstream p38 MAPK pathways.
舌骨肌功能不全是上气道扩张肌之一，是阻塞性睡眠呼吸暂停低通气综合征（OSAHS）的重要原因。有报道称，雌激素可抑制低氧诱导因子-1α（HIF-1α）在低氧环境下的表达，调节其靶基因，对慢性间歇性低氧（CIH）中的舌骨发挥保护作用。本研究旨在探讨 17β-雌二醇（E2）和白藜芦醇二聚体（RD）对 HIF-1α 的作用及其机制。分离培养小鼠舌骨肌成肌细胞，采用雌激素受体α（ERα）shRNA 慢病毒进行基因敲低。然后采用 MTT 法测定 E2 和 RD 对细胞活力的影响。将不同组细胞用不同的药物（E2 或 RD，或 E2 和 SB203580）处理，在常氧或缺氧条件下孵育 24 h，然后检测 HIF-1α、ERα、ERβ、总 p38 MAPK 和磷酸化 p38 MAPK 的表达水平。结果发现，E2 和 RD 均能抑制低氧诱导的 HIF-1α 在 mRNA 和蛋白水平的过度表达，而 RNAi 基因沉默可消除 ERα 的作用。此外，我们发现 E2 通过激活下游的 p38 MAPK 通路抑制 HIF-1α 的表达。综上所述，ERα 可能通过激活下游的 p38 MAPK 通路，使 E2 或 RD 下调 HIF-1α。
