Ren Jie, Liu Wei, Deng Yan, Li Guang-Cai, Pan Yue-Ying, Xie Sheng, Jin Meng, Liu Hui-Guo
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China.
The Third Hospital Affiliated to Kunming Medical University, No. 174 People's West Road, Kunming, 650106, China.
Sleep Breath. 2017 Sep;21(3):679-689. doi: 10.1007/s11325-017-1479-4. Epub 2017 Feb 11.
Endoplasmic reticulum (ER) stress is known to play key roles in the development of endothelial cell apoptosis induced by chronic intermittent hypoxia (CIH), and the angiotensin II-phospholipase C-inositol-1,4,5-triphosphate (AngII-PLC-IP3) pathway has been demonstrated to induce ER stress. To explore whether the AngII-PLC-IP3 pathway is involved in the vascular damage induced by CIH, we examined whether the AngII-PLC-IP3 pathway is involved in ER stress induced by CIH and whether losartan, a selective angiotensin II type 1 receptor (AT1R) blocker, could suppress endothelial cell apoptosis induced by CIH.
Adult male Sprague Dawley rats were subjected to 8 h/day of intermittent hypoxia/normoxia, with or without losartan, a selective AT1R blocker, and/or U73122, a selective PLC inhibitor, for 8 weeks. Endothelial cell apoptosis, ER stress markers, and levels of PLC-γ1 and IP3R expression were determined.
Losartan prevented increases in PLC-γ1 and IP3R protein levels and inhibited ER stress markers induced by CIH. Addition of U73122 reproduced all the protective effects of losartan. Losartan administration before CIH significantly ameliorated CIH-induced endothelial cell apoptosis.
This study showed that the AngII-PLC-IP3 pathway is involved in ER stress induced by CIH and that pre-losartan administration ameliorates endothelial cell apoptosis following CIH partly via inhibition of the AngII-PLC-IP3 pathway and ER stress.
已知内质网（ER）应激在慢性间歇性缺氧（CIH）诱导的内皮细胞凋亡发展过程中起关键作用，并且已证实血管紧张素II - 磷脂酶C - 肌醇 - 1,4,5 - 三磷酸（AngII - PLC - IP3）途径可诱导ER应激。为了探究AngII - PLC - IP3途径是否参与CIH诱导的血管损伤，我们检测了AngII - PLC - IP3途径是否参与CIH诱导的ER应激，以及选择性血管紧张素II 1型受体（AT1R）阻滞剂氯沙坦是否能抑制CIH诱导的内皮细胞凋亡。
成年雄性Sprague Dawley大鼠每天接受8小时的间歇性缺氧/常氧处理，同时给予或不给予选择性AT1R阻滞剂氯沙坦和/或选择性PLC抑制剂U73122，持续8周。测定内皮细胞凋亡、ER应激标志物以及PLC - γ1和IP3R的表达水平。
氯沙坦可防止PLC - γ1和IP3R蛋白水平升高，并抑制CIH诱导的ER应激标志物。添加U73122可重现氯沙坦的所有保护作用。在CIH之前给予氯沙坦可显著改善CIH诱导的内皮细胞凋亡。
本研究表明，AngII - PLC - IP3途径参与CIH诱导的ER应激，并且预先给予氯沙坦可部分通过抑制AngII - PLC - IP3途径和ER应激来改善CIH后的内皮细胞凋亡。
