Lawrence D. Longo MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Drug Discov Today. 2021 Nov;26(11):2754-2773. doi: 10.1016/j.drudis.2021.07.011. Epub 2021 Jul 22.
Chronic hypoxia is a common cause of pulmonary hypertension, preeclampsia, and intrauterine growth restriction (IUGR). The molecular mechanisms underlying these diseases are not completely understood. Chronic hypoxia may induce the generation of reactive oxygen species (ROS) in mitochondria, promote endoplasmic reticulum (ER) stress, and result in the integrated stress response (ISR) in the pulmonary artery and uteroplacental tissues. Numerous studies have implicated hypoxia-inducible factors (HIFs), oxidative stress, and ER stress/unfolded protein response (UPR) in the development of pulmonary hypertension, preeclampsia and IUGR. This review highlights the roles of HIFs, mitochondria-derived ROS and UPR, as well as their interplay, in the pathogenesis of pulmonary hypertension and preeclampsia, and their implications in drug development.
慢性缺氧是肺动脉高压、先兆子痫和宫内生长受限(IUGR)的常见原因。这些疾病的分子机制尚不完全清楚。慢性缺氧可能在肺血管和胎盘组织中诱导线粒体中活性氧(ROS)的产生,促进内质网(ER)应激,并导致综合应激反应(ISR)。许多研究表明,缺氧诱导因子(HIFs)、氧化应激和 ER 应激/未折叠蛋白反应(UPR)在肺动脉高压、先兆子痫和 IUGR 的发生发展中起作用。本综述强调了 HIFs、线粒体衍生的 ROS 和 UPR 及其相互作用在肺动脉高压和先兆子痫发病机制中的作用,以及它们在药物开发中的意义。