Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn

Kathryn N. Farrow; Stephen Wedgwood; Keng Jin Lee; Lyubov Czech; Sylvia F. Gugino; Satyan Lakshminrusimha; Paul T. Schumacker; Robin H. Steinhorn

doi:10.1016/j.resp.2010.08.018

Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn

Kathryn N. Farrow^*, Stephen Wedgwood, Keng Jin Lee, Lyubov Czech, Sylvia F. Gugino, Satyan Lakshminrusimha, Paul T. Schumacker, Robin H. Steinhorn

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Review article › peer-review

69 Scopus citations

Abstract

In the pulmonary vasculature, phosphodiesterase-5 (PDE5) degrades cGMP and inhibits nitric oxide-mediated, cGMP-dependent vasorelaxation. We previously reported that ventilation with 100% O₂ increased PDE5 activity in pulmonary arteries (PAs) of pulmonary hypertension lambs (PPHN) more than in control lambs. In the present study, PA smooth muscle cells (PASMCs) from PPHN lambs had increased basal PDE5 activity, decreased cGMP-responsiveness to NO, and increased mitochondrial matrix oxidant stress compared to control PASMC. Hyperoxia (24h) increased PDE5 activity and mitochondrial matrix oxidant stress above baseline to a similar degree in PPHN and control PASMC. Mitochondrially targeted catalase decreased PDE5 activity at baseline and after hyperoxia in PPHN PASMC. Similarly, catalase treatment of PPHN lambs ventilated with 100% O₂ decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H₂O₂ is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN.

Original language	English (US)
Pages (from-to)	272-281
Number of pages	10
Journal	Respiratory Physiology and Neurobiology
Volume	174
Issue number	3
DOIs	https://doi.org/10.1016/j.resp.2010.08.018
State	Published - Dec 31 2010

Funding

Grants: These studies have been funded by a Northwestern University Alumnae Grant (KNF) and a Midwest Affiliate of the American Heart Association grant # 0850137Z (SW) as well as by NIH grants HL086715 (KNF), HL54705 (RHS), and HL079650 (PTS).

Keywords

CGMP
Hyperoxia
Phosphodiesterase
Pulmonary vasculature
Reactive oxygen species

ASJC Scopus subject areas

General Neuroscience
Physiology
Pulmonary and Respiratory Medicine

Access to Document

10.1016/j.resp.2010.08.018

Cite this

@article{cc7bb766e22c49d5a65bb9513d73824e,

title = "Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn",

abstract = "In the pulmonary vasculature, phosphodiesterase-5 (PDE5) degrades cGMP and inhibits nitric oxide-mediated, cGMP-dependent vasorelaxation. We previously reported that ventilation with 100% O2 increased PDE5 activity in pulmonary arteries (PAs) of pulmonary hypertension lambs (PPHN) more than in control lambs. In the present study, PA smooth muscle cells (PASMCs) from PPHN lambs had increased basal PDE5 activity, decreased cGMP-responsiveness to NO, and increased mitochondrial matrix oxidant stress compared to control PASMC. Hyperoxia (24h) increased PDE5 activity and mitochondrial matrix oxidant stress above baseline to a similar degree in PPHN and control PASMC. Mitochondrially targeted catalase decreased PDE5 activity at baseline and after hyperoxia in PPHN PASMC. Similarly, catalase treatment of PPHN lambs ventilated with 100% O2 decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H2O2 is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN.",

keywords = "CGMP, Hyperoxia, Phosphodiesterase, Pulmonary vasculature, Reactive oxygen species",

author = "Farrow, {Kathryn N.} and Stephen Wedgwood and Lee, {Keng Jin} and Lyubov Czech and Gugino, {Sylvia F.} and Satyan Lakshminrusimha and Schumacker, {Paul T.} and Steinhorn, {Robin H.}",

note = "Funding Information: Grants: These studies have been funded by a Northwestern University Alumnae Grant (KNF) and a Midwest Affiliate of the American Heart Association grant # 0850137Z (SW) as well as by NIH grants HL086715 (KNF), HL54705 (RHS), and HL079650 (PTS).",

year = "2010",

month = dec,

day = "31",

doi = "10.1016/j.resp.2010.08.018",

language = "English (US)",

volume = "174",

pages = "272--281",

journal = "Respiratory Physiology and Neurobiology",

issn = "1569-9048",

publisher = "Elsevier B.V.",

number = "3",

}

TY - JOUR

T1 - Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn

AU - Farrow, Kathryn N.

AU - Wedgwood, Stephen

AU - Lee, Keng Jin

AU - Czech, Lyubov

AU - Gugino, Sylvia F.

AU - Lakshminrusimha, Satyan

AU - Schumacker, Paul T.

AU - Steinhorn, Robin H.

N1 - Funding Information: Grants: These studies have been funded by a Northwestern University Alumnae Grant (KNF) and a Midwest Affiliate of the American Heart Association grant # 0850137Z (SW) as well as by NIH grants HL086715 (KNF), HL54705 (RHS), and HL079650 (PTS).

PY - 2010/12/31

Y1 - 2010/12/31

N2 - In the pulmonary vasculature, phosphodiesterase-5 (PDE5) degrades cGMP and inhibits nitric oxide-mediated, cGMP-dependent vasorelaxation. We previously reported that ventilation with 100% O2 increased PDE5 activity in pulmonary arteries (PAs) of pulmonary hypertension lambs (PPHN) more than in control lambs. In the present study, PA smooth muscle cells (PASMCs) from PPHN lambs had increased basal PDE5 activity, decreased cGMP-responsiveness to NO, and increased mitochondrial matrix oxidant stress compared to control PASMC. Hyperoxia (24h) increased PDE5 activity and mitochondrial matrix oxidant stress above baseline to a similar degree in PPHN and control PASMC. Mitochondrially targeted catalase decreased PDE5 activity at baseline and after hyperoxia in PPHN PASMC. Similarly, catalase treatment of PPHN lambs ventilated with 100% O2 decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H2O2 is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN.

AB - In the pulmonary vasculature, phosphodiesterase-5 (PDE5) degrades cGMP and inhibits nitric oxide-mediated, cGMP-dependent vasorelaxation. We previously reported that ventilation with 100% O2 increased PDE5 activity in pulmonary arteries (PAs) of pulmonary hypertension lambs (PPHN) more than in control lambs. In the present study, PA smooth muscle cells (PASMCs) from PPHN lambs had increased basal PDE5 activity, decreased cGMP-responsiveness to NO, and increased mitochondrial matrix oxidant stress compared to control PASMC. Hyperoxia (24h) increased PDE5 activity and mitochondrial matrix oxidant stress above baseline to a similar degree in PPHN and control PASMC. Mitochondrially targeted catalase decreased PDE5 activity at baseline and after hyperoxia in PPHN PASMC. Similarly, catalase treatment of PPHN lambs ventilated with 100% O2 decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H2O2 is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN.

KW - CGMP

KW - Hyperoxia

KW - Phosphodiesterase

KW - Pulmonary vasculature

KW - Reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=78449308187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78449308187&partnerID=8YFLogxK

U2 - 10.1016/j.resp.2010.08.018

DO - 10.1016/j.resp.2010.08.018

M3 - Review article

C2 - 20804862

AN - SCOPUS:78449308187

SN - 1569-9048

VL - 174

SP - 272

EP - 281

JO - Respiratory Physiology and Neurobiology

JF - Respiratory Physiology and Neurobiology

IS - 3

ER -

Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this