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

Wedgwood S, Lakshminrusimha S, Schumacker PT, Steinhorn RH - Front Pharmacol (2015)

Bottom Line: Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC.Hypoxia substantially amplifies HIF activity in PPHN vascular cells.Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California Davis Medical Center Sacramento, CA, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed HIF signaling pathway in PPHN. PPHN increases mitochondrial ROS (Mito ROS) in smooth muscle cells, resulting in an increase in cytosolic ROS. This increases NFκB and HIF activities, leading to increased expression of target genes including NADPH oxidases (Nox). This stimulates a feed forward mechanism that gives a sustained increase in Cyto ROS. PPHN also increases HIF activity in endothelial cells, leading to an increase in expression and release of ET-1. ET-1 activates ETA receptors (ETAR) on adjacent smooth muscle cells, leading to vasoconstriction and increased cytosolic ROS. Cytosolic ROS can stimulate vascular remodeling and vasoconstriction as discussed in the text.
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Figure 5: Proposed HIF signaling pathway in PPHN. PPHN increases mitochondrial ROS (Mito ROS) in smooth muscle cells, resulting in an increase in cytosolic ROS. This increases NFκB and HIF activities, leading to increased expression of target genes including NADPH oxidases (Nox). This stimulates a feed forward mechanism that gives a sustained increase in Cyto ROS. PPHN also increases HIF activity in endothelial cells, leading to an increase in expression and release of ET-1. ET-1 activates ETA receptors (ETAR) on adjacent smooth muscle cells, leading to vasoconstriction and increased cytosolic ROS. Cytosolic ROS can stimulate vascular remodeling and vasoconstriction as discussed in the text.

Mentions: Newborns with PPHN that die shortly after birth display extreme hypertensive structural remodeling (Geggel and Reid, 1984), suggesting that the most severe cases of disease stem from chronic intrauterine stress. Determining the intrauterine events that alter pulmonary vascular reactivity and structure is essential to improve early detection and treatment. In this study we identified elevated HIF-1α expression in the lungs (Figure 1), and elevated HIF activity in PASMC (Figure 2), as potential regulators of abnormal gene expression in PPHN lambs. Antenatal surgical closure of the ductus arteriosus results in a sustained elevation of pulmonary arterial pressure in PPHN lambs (Storme et al., 1999). Cyclic stretch mimics increased pulmonary artery pressure, and in the current study we found that cyclic stretch increased HIF activity in PASMC isolated from control lambs via mechanisms involving mitochondrial complex III (Figure 3) and NFκB (Figure 4). Targeting the signaling pathways that stimulate HIF activity and the genes that are upregulated by HIFs (Figure 5) may represent a novel strategy for the treatment of PPHN (Table 1).


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

Wedgwood S, Lakshminrusimha S, Schumacker PT, Steinhorn RH - Front Pharmacol (2015)

Proposed HIF signaling pathway in PPHN. PPHN increases mitochondrial ROS (Mito ROS) in smooth muscle cells, resulting in an increase in cytosolic ROS. This increases NFκB and HIF activities, leading to increased expression of target genes including NADPH oxidases (Nox). This stimulates a feed forward mechanism that gives a sustained increase in Cyto ROS. PPHN also increases HIF activity in endothelial cells, leading to an increase in expression and release of ET-1. ET-1 activates ETA receptors (ETAR) on adjacent smooth muscle cells, leading to vasoconstriction and increased cytosolic ROS. Cytosolic ROS can stimulate vascular remodeling and vasoconstriction as discussed in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356070&req=5

Figure 5: Proposed HIF signaling pathway in PPHN. PPHN increases mitochondrial ROS (Mito ROS) in smooth muscle cells, resulting in an increase in cytosolic ROS. This increases NFκB and HIF activities, leading to increased expression of target genes including NADPH oxidases (Nox). This stimulates a feed forward mechanism that gives a sustained increase in Cyto ROS. PPHN also increases HIF activity in endothelial cells, leading to an increase in expression and release of ET-1. ET-1 activates ETA receptors (ETAR) on adjacent smooth muscle cells, leading to vasoconstriction and increased cytosolic ROS. Cytosolic ROS can stimulate vascular remodeling and vasoconstriction as discussed in the text.
Mentions: Newborns with PPHN that die shortly after birth display extreme hypertensive structural remodeling (Geggel and Reid, 1984), suggesting that the most severe cases of disease stem from chronic intrauterine stress. Determining the intrauterine events that alter pulmonary vascular reactivity and structure is essential to improve early detection and treatment. In this study we identified elevated HIF-1α expression in the lungs (Figure 1), and elevated HIF activity in PASMC (Figure 2), as potential regulators of abnormal gene expression in PPHN lambs. Antenatal surgical closure of the ductus arteriosus results in a sustained elevation of pulmonary arterial pressure in PPHN lambs (Storme et al., 1999). Cyclic stretch mimics increased pulmonary artery pressure, and in the current study we found that cyclic stretch increased HIF activity in PASMC isolated from control lambs via mechanisms involving mitochondrial complex III (Figure 3) and NFκB (Figure 4). Targeting the signaling pathways that stimulate HIF activity and the genes that are upregulated by HIFs (Figure 5) may represent a novel strategy for the treatment of PPHN (Table 1).

Bottom Line: Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC.Hypoxia substantially amplifies HIF activity in PPHN vascular cells.Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of California Davis Medical Center Sacramento, CA, USA.

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.

No MeSH data available.


Related in: MedlinePlus