Hypoxia-inducible factor signaling in pulmonary hypertension
Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai
Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai
View: Text | PDF
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

×

Figure 3

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

Options: View larger image (or click on image) Download as PowerPoint
HIF signaling in PH: Upstream and downstream modulators in pulmonary art...
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.