Hypoxia and the integrated stress response promote pulmonary hypertension and preeclampsia: Implications in drug development

• Published in: Drug discovery today Vol. 26; no. 11; pp. 2754 - 2773
• Main Authors: Hu, Xiang-Qun, Zhang, Lubo
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2021
• Subjects: Drug Development; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Female; Fetal Growth Retardation - drug therapy; Fetal Growth Retardation - metabolism; Fetal Growth Retardation - physiopathology; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - physiopathology; Hypoxia; Hypoxia - metabolism; Integrated stress response; Mitochondria; Mitochondria - metabolism; Oxidative Stress; Placental Circulation; Pre-Eclampsia - drug therapy; Pre-Eclampsia - metabolism; Pre-Eclampsia - physiopathology; Preeclampsia; Pregnancy; Pulmonary hypertension; Reactive oxygen species; Reactive Oxygen Species - metabolism; Stress, Physiological - physiology; Unfolded Protein Response; Vascular Remodeling; HO; RVSP; COMT; ERO1; Vascular remodeling; NF-κB; Mitochondria; Integrated stress response; mitoKATP; UPR; BKCa; mTOR; CHOP; PASMC; PEPT1; GCN2; VSMCs; GPX1; RUPP; TRPC1; mitoQ; SDHD; IPAH; ER; eIF2α; ERAD; TCA; IUGR; Preeclampsia; NOX; PKR; ROS; MAM; NDUFS3; Hypoxia; VDAC1; COX4-2; Endoplasmic reticulum; ATF6; ISCU; Reactive oxygen species; EVT; O2; IP3R; TUDCA; BiP; NFATc2; LDH-A; PERK; PHD; sFlt; Unfolded protein response; NADH; PDI; Nrf2; UCP2; VHL; GSH; PlGF; RyR2; XBP1; HIF; FAD; ISR; AKT; PAEC; siRNA; Pulmonary hypertension; SOD1; TC; CTB; ETC; mitoROS; PAH; TRPV4; IRE1α; Grp78; PRX3; TRXR2; HRI; TRX2
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2021.07.011

•Hypoxia is a common cause of pulmonary hypertension and preeclampsia.•Mitochondria and endoplasmic reticulum (ER) are the main targets of the hypoxic response.•Oxidative and ER stress converge in the ISR.•The ISR contributes to pulmonary hypertension and preeclampsia.•Potential drug development may target the ISR. 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.