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 (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.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, United States. k-farrow@northwestern.edu
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: Farrow
authors.forename: Stephen
authors.initials: S
authors.lastname: Wedgwood
authors.forename: Keng Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Lyubov
authors.initials: L
authors.lastname: Czech
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Gugino
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrusimha
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
mesh_terms: 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
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D002374:Catalase; D006152:Cyclic GMP; D010100:Oxygen
references.citation: Pediatr Res. 2009 Nov;66(5):539-44
references.pmid: 19680165
references.citation: Br J Pharmacol. 2008 Nov;155(6):847-56
references.pmid: 18660830
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: J Clin Invest. 1997 Sep 15;100(6):1448-58
references.pmid: 9294110
references.citation: Pediatrics. 2006 Apr;117(4):1077-83
references.pmid: 16585301
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Oct;289(4):L660-6
references.pmid: 15937064
references.citation: J Pediatr. 1981 Jun;98(6):962-7
references.pmid: 7229803
references.citation: Pediatr Res. 1989 Mar;25(3):245-50
references.pmid: 2704590
references.citation: Mol Genet Metab. 1998 Nov;65(3):229-37
references.pmid: 9851888
references.citation: J Pediatr. 2009 Dec;155(6):841-847.e1
references.pmid: 19836028
references.citation: Am J Physiol. 1992 Oct;263(4 Pt 1):L466-70
references.pmid: 1415724
references.citation: Anesthesiology. 1999 Jul;91(1):307-10
references.pmid: 10422958
references.citation: N Engl J Med. 1997 Feb 27;336(9):597-604
references.pmid: 9036320
references.citation: J Card Fail. 2005 Aug;11(6):473-80
references.pmid: 16105639
references.citation: Am J Respir Crit Care Med. 1999 Sep;160(3):858-65
references.pmid: 10471609
references.citation: Clin Perinatol. 1999 Sep;26(3):601-19
references.pmid: 10494467
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Aug;295(2):L370-7
references.pmid: 18556800
references.citation: Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1812-20
references.pmid: 17142346
references.citation: N Engl J Med. 1997 Feb 27;336(9):605-10
references.pmid: 9032045
references.citation: Pediatrics. 2000 Jan;105(1 Pt 1):14-20
references.pmid: 10617698
references.citation: Pediatr Res. 1989 Mar;25(3):251-7
references.pmid: 2704591
references.citation: Circ Res. 2008 Feb 1;102(2):226-33
references.pmid: 17991881
references.citation: Circ Res. 2003 Apr 4;92(6):683-91
references.pmid: 12609968
references.citation: Am J Respir Crit Care Med. 2006 Dec 15;174(12):1370-7
references.pmid: 17008638
references.citation: J Clin Invest. 1993 Feb;91(2):499-508
references.pmid: 8432858
references.citation: FASEB J. 2009 Mar;23(3):783-94
references.pmid: 18948382
references.citation: Circ Res. 2010 Feb 19;106(3):526-35
references.pmid: 20019331
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Jul;299(1):L109-16
references.pmid: 20400523
references.citation: Pediatr Res. 2006 Jan;59(1):137-41
references.pmid: 16326983
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Dec;295(6):L979-87
references.pmid: 18790993
references.citation: Int J Biochem Cell Biol. 2009 May;41(5):1002-5
references.pmid: 18992840
references.citation: J Biol Chem. 2004 Mar 26;279(13):13044-53
references.pmid: 14722062
references.citation: Crit Care Med. 2004 Dec;32(12):2496-501
references.pmid: 15599157
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Chest. 1988 Mar;93(3 Suppl):133S-138S
references.pmid: 3277815
references.citation: N Engl J Med. 2000 Feb 17;342(7):469-74
references.pmid: 10675427
references.citation: Am J Respir Crit Care Med. 1998 Jul;158(1):279-88
references.pmid: 9655741
references.citation: Pediatrics. 2001 Apr;107(4):642-7
references.pmid: 11335737