Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells

Kathryn N. Farrow, Beezly S. Groh, Paul T. Schumacker, Satyanarayana Lakshminrusimha, Lyubov Czech, Sylvia F. Gugino, James A. Russell, Robin H Steinhorn

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

In the pulmonary vasculature, cGMP concentrations are regulated in part by a cGMP-dependent phosphodiesterase (PDE), PDE5. Infants with persistent pulmonary hypertension of the newborn (PPHN) are often mechanically ventilated with high oxygen concentrations. The effects of hyperoxia on the developing pulmonary vasculature and PDE5 are largely unknown. Here, we demonstrate that exposure of fetal pulmonary artery smooth muscle cells (FPASMCs) to high levels of oxygen for 24 hours leads to decreased responsiveness to exogenous NO, as determined by a decreased intracellular cGMP response, increased PDE5 mRNA and protein expression, as well as increased PDE5 cGMP hydrolytic activity. We demonstrate that inhibition of PDE5 activity with sildenafil partially rescues cGMP responsiveness to exogenous NO. In FPASMCs, hyperoxia leads to increased oxidative stress without increasing cell death. Treatment of normoxic FPASMCs with H2O2 is sufficient to induce PDE5 expression and activity, suggesting that reactive oxygen species mediate the effects of hyperoxia in FPASMCs. In support of this mechanism, a chemical antioxidant, N-acetyl-cysteine, is sufficient to block the hyperoxia-mediated increase in PDE5 expression and activity and rescue cGMP responsiveness to exogenous NO. Finally, ventilation of healthy neonatal sheep with 100% O2 for 24 hours leads to increased PDE5 protein expression in the resistance pulmonary arteries and increased PDE5 activity in whole lung extracts. These data suggest that PDE5 expression and activity play a critical role in modulating neonatal pulmonary vascular tone in response to common clinical treatments for PPHN, such as oxygen and inhaled NO.

Original languageEnglish (US)
Pages (from-to)226-233
Number of pages8
JournalCirculation Research
Volume102
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

Fingerprint

Type 5 Cyclic Nucleotide Phosphodiesterases
Hyperoxia
Pulmonary Artery
Smooth Muscle Myocytes
Sheep
Persistent Fetal Circulation Syndrome
Lung
Oxygen
Cysteine
Blood Vessels
Ventilation
Reactive Oxygen Species
Proteins
Oxidative Stress
Cell Death
Antioxidants
Messenger RNA
Therapeutics

Keywords

  • Cyclic GMP
  • Persistent pulmonary hypertension of the newborn
  • Phosphodiesterases
  • Pulmonary circulation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. / Farrow, Kathryn N.; Groh, Beezly S.; Schumacker, Paul T.; Lakshminrusimha, Satyanarayana; Czech, Lyubov; Gugino, Sylvia F.; Russell, James A.; Steinhorn, Robin H.

In: Circulation Research, Vol. 102, No. 2, 02.2008, p. 226-233.

Research output: Contribution to journalArticle

Farrow, Kathryn N. ; Groh, Beezly S. ; Schumacker, Paul T. ; Lakshminrusimha, Satyanarayana ; Czech, Lyubov ; Gugino, Sylvia F. ; Russell, James A. ; Steinhorn, Robin H. / Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. In: Circulation Research. 2008 ; Vol. 102, No. 2. pp. 226-233.
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AU - Groh, Beezly S.

AU - Schumacker, Paul T.

AU - Lakshminrusimha, Satyanarayana

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