Influence of hypoxia on nitric oxide synthase activity and gene expression in children with congenital heart disease: a novel pathophysiological adaptive mechanism.
BACKGROUND
Chronic hypoxia has been shown to modulate nitric oxide (NO) responses in different cell models, but the relationship between hypoxia and NO synthase (NOS) regulation in humans was not studied. We studied the relationship between endothelial and inducible NOS (eNOS and iNOS) activities and expression and chronic hypoxia in children with cyanotic and acyanotic congenital heart defects.


RESULTS
Right atrial tissue was excised from 18 patients during cardiac surgery. eNOS and iNOS activities were measured by conversion of L-[H(3)]arginine to L-[H(3)]citrulline. Gene expression of eNOS and iNOS was quantified by competitive reverse transcription-polymerase chain reaction. The eNOS activity and expression were significantly reduced in cyanotic hearts compared with acyanotic hearts: 0.38+/-0.14 versus 1.06+/-0.11 pmol. mg(-1). min(-1) (P<0.0001) and 0.54+/-0.08 versus 0.80+/-0.10 relative optical density (ROD) of cDNA (P<0.0001), respectively. In contrast, iNOS activity and expression were significantly higher in cyanotic than in acyanotic children: 7.04+/-1.20 versus 4.17+/-1.10 pmol. mg(-1). min(-1) (P<0.0001) and 2.55+/-0.11 versus 1.91+/-0.18 ROD of cDNA (P<0.0001), respectively.


CONCLUSIONS
Hypoxia downregulates eNOS activity and gene expression in cardiac tissue from patients with cyanotic congenital heart defects. By contrast, iNOS activity and expression are increased in cyanotic children and may represent an alternative mechanism to counteract the effects of hypoxia in the cardiovascular system. Therefore, a novel adaptive mechanism during hypoxia is suggested.
Ferreiro
C R
CR
Atherosclerosis Unit, Heart Institute, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil.
Chagas
A C
AC
Carvalho
M H
MH
Dantas
A P
AP
Jatene
M B
MB
Bento De Souza
L C
LC
Lemos Da Luz
P
P
D000222:Adaptation, Physiological; D000293:Adolescent; D020517:Atrial Appendage / Q000201:enzymology; D001784:Blood Gas Analysis; D002648:Child; D002675:Child, Preschool; D003490:Cyanosis / Q000201:enzymology* / Q000209:etiology; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006325:Heart Atria / Q000201:enzymology; D006330:Heart Defects, Congenital / Q000150:complications / Q000201:enzymology* / Q000601:surgery; D006439:Hemodynamics; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020133:Reverse Transcriptase Polymerase Chain Reaction
C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III