Roles of HIF1 and HIF2 in pulmonary hypertension: it all depends on the context

Abstract

@ERSpublications HIF1 and HIF2 can play complementary, opposing or unrelated roles in mediating the response to low oxygen levels in different cell types. This study shows HIF2 plays a dominant role in mediating the development of PH in response to environmental hypoxia. http://bit.ly/2Cy46sR Cite this article as: Waypa GB, Schumacker PT. Roles of HIF1 and HIF2 in pulmonary hypertension: it all depends on the context. Eur Respir J 2019; 54: 1901929 [https://doi.org/10.1183/13993003.01929-2019].Pulmonary hypertension (PH) is a diverse collection of vascular disorders that cause remodelling of small pulmonary arteries, resulting in increases in pulmonary vascular resistance and pulmonary arterial pressure. The World Health Organization classifies these disorders into five groups. Group III includes pulmonary hypertension associated with hypoxic lung disorders such as COPD. While not everyone with COPD develops pulmonary hypertension, those who do are more likely to experience acute exacerbations, hospitalisations, and poorer outcomes. Because alveolar hypoxia is a key element driving this response, investigators have studied how chronic hypoxia contributes to the development of PH.

Network Pharmacology and Molecular Docking Analysis of Shufeiya Recipe in the Treatment of Pulmonary Hypertension

“…ERK activation can promote the proliferation of pulmonary artery fibroblasts, while Shufeiya recipe can downregulate the expression levels of Ras, p-MEK1/2, p-ERK1/2, and c-fos proteins in the ERK signaling pathway, thereby inhibitting PAECs fibrosis [ 5 ]. Activation of the HIF-1 signaling pathway in PAECs can promote the proliferation of pulmonary artery medial cells, and the expression of factors such as endothelin 1 [ 21 , 29 ]. The Toll-like receptor signaling pathway is closely related to the proliferation, apoptosis, migration, and interstitial transition of PAECs [ 22 , 30 ].…”

Intermittent short‐duration reoxygenation protects against simulated high altitude‐induced pulmonary hypertension in rats

“…43 This HIF "switch" results in HIF-1 and HIF-2 playing divergent but complementary roles during the hypoxic response of tissues under pathophysiological conditions. 41,42,44 In our study, we used cell models to detect the effects of intermittent reoxygenation on HIF-1α and HIF-2α protein expression in HPASMCs. We found that intermittent short-duration reoxygenation disrupted the "switch" of HIF-1α and HIF-2α, which was probably one of the reasons why intermittent short-duration reoxygenation had a protective role in pulmonary arterial remodeling induced by hypoxia.…”

“…HIF-1 drives the initial response to hypoxia, but during chronic hypoxic exposure it is HIF-2 that plays the major role in driving the hypoxic responses. 41,42 It's reported that when the HPASMCS is exposed to hypoxia, HIF-1α will rapidly accumulate and reach maximal levels from 2 to 6 hours of hypoxia. Afterwards, HIF-1a abundance was reduced and the HIF-2α reaches maximal levels at about 8 hours of hypoxia and remains elevated for more than 48 hours.…”

Endotyping COPD: hypoxia-inducible factor-2 as a molecular “switch” between the vascular and airway phenotypes?

“…Previously, beneficial effects of HIF-2α inhibition on the development of PH were shown in different animal models [ 49 ]. Although HIF-1α plays an important role for HPV in pulmonary artery smooth muscle cells (PASMCs) and adventitial fibroblasts [ 110 ], endothelial HIF-2α appears to be the predominant factor in the pathogenesis of COPD-PH.…”