Increased p22phox/Nox4 expression is involved in remodeling through hydrogen peroxide signaling in experimental persistent pulmonary hypertension of the newborn

Stephen Wedgwood, Satyanarayana Lakshminrusimha, Lyubov Czech, Paul T. Schumacker, Robin H Steinhorn

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Aim: To determine if the NADPH oxidase isoform Nox4 contributes to increased H2O2 generation in persistent pulmonary hypertension of the newborn (PPHN) pulmonary arteries (PA), and to identify downstream signaling targets of Nox4 that contribute to vascular remodeling and vasoconstriction. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs, PA, and PA smooth muscle cells (PASMC) were isolated from control and PPHN lambs. Increased expression of p22phox and Nox4 in PPHN lungs, PA, and PASMC was associated with increased reactive oxygen species in PPHN PA, increased protein thiol oxidation in PPHN PASMC, and a decreased activity of extracellular superoxide dismutase (ecSOD) in the lungs and PASMC. Nox4 small interfering RNA (siRNA) decreased Nox4 expression and thiol oxidation and increased the ecSOD activity in PPHN PASMC. An increased activity of nuclear factor-kappa B (NFκB) and expression of its target gene cyclin D1 were detected in PPHN lungs, PA, and PASMC. Nox4 siRNA and catalase attenuated these increases in PASMC, and catalase decreased cyclin D1 expression in PPHN lungs. Innovation: This study demonstrates for the first time that Nox4 expression is elevated in a lamb model of neonatal pulmonary hypertension. It identifies increased NFκB and cyclin D1 expression and a decreased ecSOD activity as targets of increased Nox4 signaling. Conclusion: PPHN increases p22phox and Nox4 expression and activity resulting in elevated H2O2 levels in PPHN PA. Increased H2O2 induces vasoconstriction via mechanisms involving ecSOD inactivation, and stimulates vascular remodeling via NFκB activation and increased cyclin D1 expression. Approaches that inhibit the pulmonary arterial Nox4 activity may attenuate vasoconstriction and vascular remodeling in PPHN.

Original languageEnglish (US)
Pages (from-to)1765-1776
Number of pages12
JournalAntioxidants and Redox Signaling
Volume18
Issue number14
DOIs
StatePublished - May 10 2013
Externally publishedYes

Fingerprint

Persistent Fetal Circulation Syndrome
Hydrogen Peroxide
Muscle
Cyclin D1
Pulmonary Artery
Smooth Muscle Myocytes
Superoxide Dismutase
NF-kappa B
Lung
Sulfhydryl Compounds
Catalase
Small Interfering RNA
Vasoconstriction
Oxidation
NADPH Oxidase
bcl-1 Genes
Reactive Oxygen Species
Protein Isoforms
Genes
Innovation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

Increased p22phox/Nox4 expression is involved in remodeling through hydrogen peroxide signaling in experimental persistent pulmonary hypertension of the newborn. / Wedgwood, Stephen; Lakshminrusimha, Satyanarayana; Czech, Lyubov; Schumacker, Paul T.; Steinhorn, Robin H.

In: Antioxidants and Redox Signaling, Vol. 18, No. 14, 10.05.2013, p. 1765-1776.

Research output: Contribution to journalArticle

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abstract = "Aim: To determine if the NADPH oxidase isoform Nox4 contributes to increased H2O2 generation in persistent pulmonary hypertension of the newborn (PPHN) pulmonary arteries (PA), and to identify downstream signaling targets of Nox4 that contribute to vascular remodeling and vasoconstriction. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs, PA, and PA smooth muscle cells (PASMC) were isolated from control and PPHN lambs. Increased expression of p22phox and Nox4 in PPHN lungs, PA, and PASMC was associated with increased reactive oxygen species in PPHN PA, increased protein thiol oxidation in PPHN PASMC, and a decreased activity of extracellular superoxide dismutase (ecSOD) in the lungs and PASMC. Nox4 small interfering RNA (siRNA) decreased Nox4 expression and thiol oxidation and increased the ecSOD activity in PPHN PASMC. An increased activity of nuclear factor-kappa B (NFκB) and expression of its target gene cyclin D1 were detected in PPHN lungs, PA, and PASMC. Nox4 siRNA and catalase attenuated these increases in PASMC, and catalase decreased cyclin D1 expression in PPHN lungs. Innovation: This study demonstrates for the first time that Nox4 expression is elevated in a lamb model of neonatal pulmonary hypertension. It identifies increased NFκB and cyclin D1 expression and a decreased ecSOD activity as targets of increased Nox4 signaling. Conclusion: PPHN increases p22phox and Nox4 expression and activity resulting in elevated H2O2 levels in PPHN PA. Increased H2O2 induces vasoconstriction via mechanisms involving ecSOD inactivation, and stimulates vascular remodeling via NFκB activation and increased cyclin D1 expression. Approaches that inhibit the pulmonary arterial Nox4 activity may attenuate vasoconstriction and vascular remodeling in PPHN.",
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