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.

Figure 1. Emerging concepts of HIF signaling in pulmonary hypertension.

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; α_1βAR, 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.

Figure 2. HIF signaling in PH: upstream and downstream modulators in pulmonary artery endothelial cells.

Vasomodulatory, mitochondrial, and inflammatory growth factors and epigenetic abnormalities associated with PH regulate HIF isoform stability and transcriptional activity in pulmonary artery endothelial cells (PAECs). Subsequently, HIF isoforms transcriptionally activate a series of genes that participate in vascular tone, angiogenesis, metabolism, and cell proliferation. Long black lines with arrows indicate an activating effect; blocked red lines, an inhibiting effect; ↑, activation or upregulation; ↓, inactivation or downregulation. TFAM, mitochondrial transcription factor A; PlGF, placental growth factor; EPOR, erythropoietin receptor; ET_A/B, endothelin receptor type A and B; sONE, antisense mRNA; ADMA, asymmetric dimethylarginine; Cul2, Cullin 2; ATOH8, atonal BHLH transcription factor 8; ISCU1/2, iron-sulfur (Fe-S) cluster assembly proteins 1 and 2; PGK1, phosphoglycerate kinase 1; PKM, pyruvate kinase M.

Figure 3. HIF signaling in PH: Upstream and downstream modulators in pulmonary artery smooth muscle cells.

Signaling pathways associated with PH such as hypoxia, vasomodulation, growth factors, mechanical stress, and oxidative stress pathways regulate HIF isoform stability and transcriptional activity in PASMCs. This regulates genes related to cell proliferation and synthetic phenotypes, as well as genes related to Ca2+ modulation/ion channels, oxidative stress, mitochondrial fragmentation, and the renin-angiotensin-aldosterone system (RAAS) system. Long black lines with arrows indicate an activating effect; blocked red lines, an inhibiting effect; ↑, activation or upregulation; ↓, inactivation or downregulation. C-III, mitochondrial complex III; SIRT3, Sirtuin 3; TRPC6, transient receptor potential cation channel subfamily C member 1 or 6; FGFR, fibroblast growth factor receptor; Ang-I, angiotensin I; Ang-II, angiotensin II; Ang-(1-7), angiotensin (1-7); Mas, Ang-(1-7) receptor; ATR1/2, angiotensin receptor type 1 and 2; ACE, angiotensin converting enzyme; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol trisphosphate; DAG, diacylglycerol; O2-, superoxide anion; PKCα, protein kinase C alpha; PAK1, P21 activated kinase 1; SENP-1, sentrin-specific protease 1.