Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension.
Endothelial nitric oxide (NO) synthase (eNOS) expression and activity are decreased in fetal lambs with persistent pulmonary hypertension (PPHN). We sought to determine the impact of mechanical ventilation with O(2) with or without inhaled NO (iNO) or recombinant human SOD (rhSOD) on eNOS in the ductal ligation model of PPHN. PPHN lambs and age-matched controls were ventilated with 100% O(2) for 24 h alone or combined with 20 ppm iNO continuously or a single dose of rhSOD (5 mg/kg) given intratracheally at delivery. In 1-day spontaneously breathing lambs, eNOS expression in resistance pulmonary arteries increased relative to fetal levels. eNOS expression increased in control lambs ventilated with 100% O(2), but not in PPHN lambs. Addition of iNO or rhSOD increased eNOS expression and decreased generation of reactive oxygen species (ROS) in PPHN lambs relative to those ventilated with 100% O(2) alone. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH(4)), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. These data suggest that ventilation of PPHN lambs with 100% O(2) increases ROS production, blunts postnatal increases in eNOS expression, and decreases available BH(4) in PPHN lambs. Although the addition of iNO or rhSOD diminished ROS production and increased eNOS expression, only rhSOD improved eNOS function and levels of available BH(4). Thus therapies designed to decrease oxidative stress and restore eNOS coupling, such as rhSOD, may prove useful in the treatment of PPHN in newborn infants.
Farrow
Kathryn N
KN
Dept. of Pediatrics, Northwestern Univ. Feinberg School of Medicine, 303 E. Chicago Ave., Ward 12-196, Chicago, IL 60611, USA. k-farrow@northwestern.edu
Lakshminrusimha
Satyan
S
Reda
William J
WJ
Wedgwood
Stephen
S
Czech
Lyubov
L
Gugino
Sylvia F
SF
Davis
Jonathan M
JM
Russell
James A
JA
Steinhorn
Robin H
RH
D000818:Animals; D000831:Animals, Newborn; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D006136:GTP Cyclohydrolase / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects; D010547:Persistent Fetal Circulation Syndrome / Q000188:drug therapy* / Q000201:enzymology; D011651:Pulmonary Artery / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012121:Respiration, Artificial; D012756:Sheep; D013482:Superoxide Dismutase / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D001708:Biopterins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D006136:GTP Cyclohydrolase; C003402:sapropterin
Pediatr Res. 1990 Apr;27(4 Pt 1):372-8
2342829
Am J Respir Crit Care Med. 2003 Jun 15;167(12):1600-19
12796054
J Clin Invest. 1997 Sep 15;100(6):1448-58
9294110
Am J Respir Cell Mol Biol. 1999 Nov;21(5):629-36
10536122
J Appl Physiol (1985). 1992 Jul;73(1):213-8
1506372
Pediatr Res. 2006 Jan;59(1):137-41
16326983
Biochem J. 2001 Aug 1;357(Pt 3):593-615
11463332
Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1069-77
16684951
Pediatr Res. 2008 Jan;63(1):67-72
18043518
J Pediatr. 1981 Jun;98(6):962-7
7229803
Circulation. 2005 Oct 18;112(16):2477-86
16230500
Clin Perinatol. 1996 Dec;23(4):711-26
8982566
N Engl J Med. 1997 Feb 27;336(9):597-604
9036320
Free Radic Biol Med. 2003 Aug 1;35(3):236-56
12885586
Int J Biochem Cell Biol. 2008;40(4):755-65
18054268
Am J Respir Cell Mol Biol. 1994 Oct;11(4):432-8
7522486
Anal Biochem. 1976 May 7;72:248-54
942051
Am J Physiol. 1993 Jun;264(6 Pt 2):H2162-7
8322947
Annu Rev Physiol. 2002;64:749-74
11826287
Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1812-20
17142346
N Engl J Med. 1997 Feb 27;336(9):605-10
9032045
Pediatrics. 2000 Jan;105(1 Pt 1):14-20
10617698
Circulation. 2003 Oct 21;108(16):1912-6
14568884
Am J Physiol. 1997 May;272(5 Pt 1):L1005-12
9176267
Pediatr Res. 1989 Mar;25(3):251-7
2704591
Circ Res. 2008 Feb 1;102(2):226-33
17991881
Circ Res. 2003 Apr 4;92(6):683-91
12609968
Am J Respir Crit Care Med. 2006 Dec 15;174(12):1370-7
17008638
Circ Res. 1999 Oct 15;85(8):753-66
10521248
Circulation. 2005 Apr 26;111(16):2086-90
15824199
Am J Physiol Lung Cell Mol Physiol. 2006 Feb;290(2):L232-41
16143585
Free Radic Biol Med. 2003 May 15;34(10):1343-52
12726922
Pediatrics. 2004 Mar;113(3 Pt 1):559-64
14993550
Circulation. 2005 Apr 26;111(16):2126-33
15824200
Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1367-73
15166009
Am J Physiol Lung Cell Mol Physiol. 2005 Oct;289(4):L660-6
15937064
Crit Care Med. 2004 Dec;32(12):2496-501
15599157
Methods. 2001 Dec;25(4):402-8
11846609
Chest. 1988 Mar;93(3 Suppl):133S-138S
3277815
N Engl J Med. 2000 Feb 17;342(7):469-74
10675427
J Clin Invest. 2003 Apr;111(8):1201-9
12697739
Pediatr Res. 2006 Jun;59(6):767-72
16641207
Pediatr Pulmonol. 2001 Feb;31(2):97-105
11180684
Pediatr Res. 2007 Sep;62(3):313-8
17622960
Pediatrics. 2001 Apr;107(4):642-7
11335737
DNA Cell Biol. 2003 May;22(5):317-28
12941159
Pediatr Res. 1989 Mar;25(3):245-50
2704590