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.
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% O
2
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% O
2
decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H
2
O
2
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% O
2
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% O
2
decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H
2
O
2
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
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U2 - 10.1016/j.resp.2010.08.018
DO - 10.1016/j.resp.2010.08.018
M3 - Review article
C2 - 20804862
AN - SCOPUS:78449308187
VL - 174
SP - 272
EP - 281
JO - Respiratory Physiology and Neurobiology
JF - Respiratory Physiology and Neurobiology
SN - 1569-9048
IS - 3
ER -