Hypoxia-inducible factor signaling in pulmonary hypertension
Soni Savai Pullamsetti, … , Werner Seeger, Rajkumar Savai
Soni Savai Pullamsetti, … , Werner Seeger, Rajkumar Savai
Published September 3, 2020
Citation Information: J Clin Invest. 2020;130(11):5638-5651. https://doi.org/10.1172/JCI137558.
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Review Series

Hypoxia-inducible factor signaling in pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.

Authors

Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai

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Figure 1

Emerging concepts of HIF signaling in pulmonary hypertension.

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Emerging concepts of HIF signaling in pulmonary hypertension. Emerging e...
Emerging evidence shows that many pro-PH factors apart from hypoxia, such as inflammation, mechanical stretch, oxidative stress, and genetic predisposition, converge on HIF signaling pathways, causing alterations in vascular tone, angiogenesis, metabolism, and cell survival that subsequently lead to pulmonary vascular and right ventricular remodeling. VHL, von Hippel–Lindau tumor suppressor; α1βAR, α1β-adrenergic receptor; iNOS, inducible nitric oxide synthase; HO-1, heme oxygenase-1; TRPC1, transient receptor potential canonical 1; KCNA5, potassium voltage-gated channel, shaker-related subfamily, member 5; KCNMB1, calcium-activated potassium channel subunit beta-1; PAI-1, plasminogen activator inhibitor-1; TF, transferrin; TFR, transferrin receptor; EPO, erythropoietin; PDK1, pyruvate dehydrogenase kinase 1; IGF2BP1, insulin-like growth factor 2 mRNA-binding protein 1; p21, cyclin-dependent kinase inhibitor 1; CCNG2, cyclin-G2; DEC1, deleted in esophageal cancer 1.