Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn.
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 (24 h) 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.
Farrow
Kathryn N
KN
Department of Pediatrics, Northwestern University, Chicago, IL 60611, United States. k-farrow@northwestern.edu
Wedgwood
Stephen
S
Lee
Keng Jin
KJ
Czech
Lyubov
L
Gugino
Sylvia F
SF
Lakshminrusimha
Satyan
S
Schumacker
Paul T
PT
Steinhorn
Robin H
RH
D000818:Animals; D000831:Animals, Newborn; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006041:Goats; D006801:Humans; D007118:Immunoassay / Q000379:methods; D007231:Infant, Newborn; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D010547:Persistent Fetal Circulation Syndrome / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D002374:Catalase; D006152:Cyclic GMP; D010100:Oxygen
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