Inhibitory Effects Of 17 Beta-Estradiol Or A Resveratrol Dimer On Hypoxia-Inducible Factor-1 Alpha In Genioglossus Myoblasts: Involvement Of Er Alpha And Its Downstream P38 Mapk Pathways

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-1 alpha (HIF-1 alpha) 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 17 beta-estradiol (E-2) and a resveratrol dimer (RD) on HIF-1 alpha and the underlying mechanism. Mouse genioglossus myoblasts were isolated and cultured, and the estrogen receptor alpha (ER alpha) shRNA lentivirus was used for gene knockdown. Then MTT assay was used to determine the effects of E-2 and RD on the viability of the cells. Cells in different groups were treated with different agents (E-2, or RD, or E-2 and SB203580), incubated under normoxia or hypoxia for 24 h, and then expression levels of HIF-1 alpha, ER alpha, ER beta, total-p38 MAPK and phospho-p38 MAPK were detected. We observed that both E-2 and RD inhibited the overexpression of HIF-1 alpha induced by hypoxia at the mRNA and protein levels, and these effects were eliminated by genetic silencing of ER alpha by RNAi. In addition, we found that E-2 activated p38 MAPK pathways to inhibit HIF-1 alpha expression. On the whole, ER alpha may be responsible for downregulation of HIF-1 alpha by E-2 or RD via activation of downstream p38 MAPK pathways.