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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

HIF-1α expression is increased in PPHN lungs (A) Representative blots for HIF-1α from control and PPHN lungs. Lysates from two different animals in each group are depicted. (B) Expression levels were normalized to β-actin levels and expressed as fold change relative to controls. *p < 0.05. N = 4 animals.
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Figure 1: HIF-1α expression is increased in PPHN lungs (A) Representative blots for HIF-1α from control and PPHN lungs. Lysates from two different animals in each group are depicted. (B) Expression levels were normalized to β-actin levels and expressed as fold change relative to controls. *p < 0.05. N = 4 animals.

Mentions: Total lung HIF-1α protein levels were increased in lung samples from PPHN lambs relative to controls as detected by Western blotting (Figure 1A). When normalized to β-actin, normoxic expression of HIF-1α was 1.6-fold higher in PPHN lungs (Figure 1B, *p < 0.05).


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

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

HIF-1α expression is increased in PPHN lungs (A) Representative blots for HIF-1α from control and PPHN lungs. Lysates from two different animals in each group are depicted. (B) Expression levels were normalized to β-actin levels and expressed as fold change relative to controls. *p < 0.05. N = 4 animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: HIF-1α expression is increased in PPHN lungs (A) Representative blots for HIF-1α from control and PPHN lungs. Lysates from two different animals in each group are depicted. (B) Expression levels were normalized to β-actin levels and expressed as fold change relative to controls. *p < 0.05. N = 4 animals.
Mentions: Total lung HIF-1α protein levels were increased in lung samples from PPHN lambs relative to controls as detected by Western blotting (Figure 1A). When normalized to β-actin, normoxic expression of HIF-1α was 1.6-fold higher in PPHN lungs (Figure 1B, *p < 0.05).

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