Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn

Stephen Wedgwood, Robin H. Steinhorn, Melisa Bunderson, Jason William, Satyan Lakshminrusimha, Lisa A. Brennan, Stephen Matthew Black

Research output: Contribution to journalArticle

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Abstract

Similar to infants born with persistent pulmonary hypertension of the newborn (PPHN), there is an increase in circulating endothelin-1 (ET-1) and decreased cGMP-mediated vasodilation in an ovine model of PPHN, These abnormalities lead to vasoconstriction and vascular remodeling. Our previous studies have demonstrated that reactive oxygen species (ROS) levels are increased in pulmonary arterial smooth muscle cells (PASMC) exposed to ET-1. Thus the initial objective of this study was to determine whether the development of pulmonary hypertension in utero is associated with elevated production of the ROS hydrogen peroxide (H2O2) and if this is associated with alterations in antioxidant capacity. Second we wished to determine whether chronic exposure of PASMC isolated from fetal lambs to H 2O2 would mimic the decrease in soluble guanylate cyclase expression observed in the ovine model of PPHN. Our results indicate that H 2O2 levels are significantly elevated in pulmonary arteries isolated from 136-day-old fetal PPHN lambs (P 0.05). In addition, we determined that catalase and glutathione peroxidase expression and activities remain unchanged. Also, we found that the overnight exposure of fetal PASMC to a H2O2-generating system resulted in significant decreases in soluble guanylate cyclase expression and nitric oxide (NO)-dependent cGMP generation (P 0.05). Finally, we demonstrated that the addition of the ROS scavenger catalase to isolated pulmonary arteries normalized the vasodilator responses to exogenous NO. As these scavengers had no effect on the vasodilator responses in pulmonary arteries isolated from age-matched control lambs this enhancement appears to be unique to PPHN. Overall our data suggest a role for H2O2 in the abnormal vasodilation associated with the pulmonary arteries of PPHN lambs.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume289
Issue number4 33-4
DOIs
StatePublished - Oct 1 2005

Fingerprint

Persistent Fetal Circulation Syndrome
Hydrogen Peroxide
Down-Regulation
Lung
Pulmonary Artery
Smooth Muscle Myocytes
Reactive Oxygen Species
Endothelin-1
Vasodilator Agents
Vasodilation
Catalase
Sheep
Nitric Oxide
Glutathione Peroxidase
Vasoconstriction
Pulmonary Hypertension
Soluble Guanylyl Cyclase
Antioxidants

Keywords

  • Guanosine 3′,5′-cyclic monophosphate
  • Reactive oxygen species
  • Vasodilation

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn. / Wedgwood, Stephen; Steinhorn, Robin H.; Bunderson, Melisa; William, Jason; Lakshminrusimha, Satyan; Brennan, Lisa A.; Black, Stephen Matthew.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 289, No. 4 33-4, 01.10.2005.

Research output: Contribution to journalArticle

Wedgwood, Stephen ; Steinhorn, Robin H. ; Bunderson, Melisa ; William, Jason ; Lakshminrusimha, Satyan ; Brennan, Lisa A. ; Black, Stephen Matthew. / Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2005 ; Vol. 289, No. 4 33-4.
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AU - Black, Stephen Matthew

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