Department of Pulmonary, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Cell Biochem. 2019 Mar;120(3):4214-4224. doi: 10.1002/jcb.27708. Epub 2018 Dec 5.
Chronic intermittent hypoxia (CIH) in obstructive sleep apnea causes damage of aortic endothelial cells, which predisposes the development of many cardiovascular diseases. Recently, both altered expression of microRNAs (miRNAs) and impaired autophagy were found to be associated with endothelial cell dysfunction in CIH. However, the exact molecular regulatory pathway has not been determined. Here, we address this question. In a mouse model of CIH, we detected significant upregulation of miR-30a, a miRNA that targets 3'-untranslated region of autophagy-associated protein 6 (Beclin-1) messenger RNA (mRNA) for suppressing the protein translation, which subsequently attenuated the endothelial cell autophagy against cell death. Indeed, unlike Beclin-1 mRNA, the Beclin-1 protein in endothelial cells did not increase after CIH. Suppression of miR-30a by expression of antisense of miR-30a significantly increased Beclin-1 levels to enhance endothelial cell autophagy in vitro and in vivo, which improved endothelial cell survival against CIH. Together, these data suggest that endothelial cell autophagy in CIH may be attenuated by miR-30a-mediated translational control of Beclin-1 as an important cause of endothelial cell dysfunction and damage.
慢性间歇性低氧（CIH）在阻塞性睡眠呼吸暂停中引起主动脉内皮细胞损伤，这易导致许多心血管疾病的发生。最近，miRNAs（miRNA）表达改变和自噬受损都与 CIH 中的内皮细胞功能障碍有关。然而，确切的分子调控途径尚未确定。在这里，我们探讨了这个问题。在 CIH 的小鼠模型中，我们检测到 miR-30a 的显著上调，miR-30a 是一种靶向自噬相关蛋白 6（Beclin-1）信使 RNA（mRNA）3'-非翻译区的 miRNA，可抑制蛋白翻译，从而减弱内皮细胞自噬以抵抗细胞死亡。实际上，与 Beclin-1 mRNA 不同，CIH 后内皮细胞中的 Beclin-1 蛋白没有增加。通过表达 miR-30a 的反义寡核苷酸抑制 miR-30a 可显著增加 Beclin-1 水平，从而增强体外和体内的内皮细胞自噬，改善内皮细胞对 CIH 的存活能力。综上所述，这些数据表明，CIH 中的内皮细胞自噬可能通过 miR-30a 介导的 Beclin-1 翻译控制减弱，这是内皮细胞功能障碍和损伤的一个重要原因。
