ET-1/PLC-IP3信号通路介导的内质网应激在慢性间歇性缺氧致血管损害中的机制研究

Among the complications caused by obstructive sleep apnea syndrome (OSAS), complications of the cardiovascular system are the most noticeable. In particular, vascular damage is considered to be the common cause of complications of the cardiovascular diseases due to OSAS, which include chronic cardiac failure and high blood pressure. Researchers have indicated that chronic intermittent hypoxia (CIH)—one of the main pathophysiological features of OSAS—can cause significant damage to vascular tissue by inducing calcium homeostasis disorders and unfolded protein response in the endoplasmic reticulum of vascular endothelial cells. In the present study, we used cell and animal models exposed to CIH as well as human studies to investigate the effects of calcium homeostasis disorders and unfolded protein response in the endoplasmic reticulum mediated by the ET-1/PLC-IP3 signaling pathway during the process of vascular damage caused by CIH. Furthermore, we specifically blocked the signal transduction of the ET-1/PLC-IP3 signaling pathway by using chemical blockers, including key signaling molecules, or via genetic tools (RNA interference, RNAi), and assessed the improvement in vascular damage or vascular endothelial cells in order to yield a indepth understanding regarding the molecular mechanisms underlying OSAS-induced vascular damage and provide novel treatment options for it.

心血管系统并发症是阻塞性睡眠呼吸暂停低通气综合征（OSAS）引起的诸多临床并发症中最引人瞩目的，血管损害被认为是包括慢性心力衰竭、高血压等在内的OSAS致心血管系统并发症共同的致病因素。研究表明OSAS的主要病理生理学特征之一慢性间歇性低氧（CIH）可以通过诱导血管内皮细胞内质网钙稳态紊乱和未折叠蛋白反应而显著损害血管组织。本研究拟通过暴露于慢性间歇性低氧环境的细胞以及动物模型，结合人体研究，旨在探讨ET-1/PLC-IP3信号通路介导的血管细胞内质网钙稳态紊乱和未折叠蛋白反应在慢性间歇性低氧致血管损害中的作用，并利用 ET-1/PLC-IP3信号通路关键信号分子的化学阻滞剂或基因手段（RNA 干扰技术,RNAi）特异性地阻断该通路的信号转导环节以了解血管或者血管内皮细胞损害的改善情况，以期为 OSAS所诱发的血管损害等提供更深入的分子机制阐释和新的治疗思路。

内质网(endoplasmic reticulum，ER)应激在慢性间歇性缺氧（chronic intermittent hypoxia，CIH）诱导的内皮细胞凋亡中起着关键作用，但CIH如何引起内质网应激，其中的机制尚不清楚。本研究探索了AngⅡ-PLC-IP3信号通路是否参与CIH诱导的血管损伤，是否可以调控CIH诱导的ER应激，以及选择性血管紧张素Ⅱ型受体 (angiotensin Ⅱ type 1 receptor，AT1R) 阻滞剂氯沙坦（losartan）是否能够抑制CIH诱导的主动脉内皮细胞凋亡。研究表明，AngⅡ-PLC-IP3信号通路参与了CIH诱导的ER应激，氯沙坦通过抑制AngⅡ-PLC-IP3信号通路改善CIH引起的主动脉内皮细胞凋亡。其次，阿托伐他汀被证实可以改善CIH引起的心肌肥厚。然而，对于阿托伐他汀调控CIH诱导的心肌肥大的机制，以及心肌肥大特异性相关的microRNAs是否参与调控尚不清楚。本研究探索了miR-31是否参与了阿托伐他汀对CIH诱导的心肌肥大的保护作用。结果表明，阿托伐他汀可能通过上调PKCε和下调miR-31保护CIH导致的心肌细胞肥大。另外，脂肪肝发展为非酒精性脂肪性肝炎(nonalcoholic steatohepatitis， NASH)与阻塞性睡眠呼吸暂停(obstructive sleep apnea syndrome，OSAS)有关。CIH导致肝损伤的机制以及褪黑素对肝损伤的调控作用尚不清楚。本研究研究了CIH导致肝损伤的机制，褪黑素对CIH引起肝损伤的调控作用，以及自噬这一信号通路是否参与其中。结果提示褪黑素通过激活SIRT1介导的自噬信号通路改善FD/CIH诱导的肝细胞损伤。