Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn.

Paul T Schumacker,Satyan Lakshminrusimha,Robin H Steinhorn,Stephen Wedgwood

doi:10.3389/fphar.2015.00047

Abstract

Background: Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood.Aim: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms.Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB.Conclusion: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.

Highlights

At birth, the lung replaces the placenta as the organ of gas exchange
Total lung hypoxia inducible factor (HIF)-1α protein levels were increased in lung samples from pulmonary hypertension of the newborn (PPHN) lambs relative to controls as detected by Western blotting (Figure 1A)
Nuclear HIF-1α protein levels were higher in PPHN vs. control pulmonary artery smooth muscle cells (PASMC) cultured in normoxia as detected by immunocytochemistry (Figure 2A)

Summary

Introduction

The lung replaces the placenta as the organ of gas exchange. When the newborn takes its first breath, the sudden increase in lung oxygenation reverses hypoxic pulmonary vasoconstriction, resulting in an 8–10 fold increase in pulmonary blood flow (Dawes et al, 1953).HIF signaling as a therapeutic target for PPHNComplex physiological and biochemical processes facilitate the fetal to newborn transition, and abnormal lung development and/or vascular dysfunction may disrupt these events. Failure to adapt to postnatal life results in persistent pulmonary hypertension of the newborn (PPHN), characterized by elevated pulmonary vascular resistance, right-to-left extrapulmonary shunting of deoxygenated blood and severe hypoxemia (Steinhorn, 2010). Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. The role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood

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