Association of neonatal hypoxia with lasting changes in left ventricular gene expression: an animal model.
OBJECTIVE
Innovations in pediatric cardiovascular surgery have resulted in significant improvements in survival for children with congenital heart disease. In adults with such disease, however, surgical morbidity and mortality remain significant. We hypothesized that hypoxemia in early life causes lasting changes in gene expression in the developing heart and that such changes may persist into later life, affecting the physiology of the adult myocardium.


METHODS
Microarray expression analyses were performed with left ventricular tissue from 10- and 90-day-old rats exposed to hypoxia (inspired oxygen fraction 0.12) for the first 10 days after birth then subsequently reared in ambient air and with tissue from age-matched rats reared entirely in ambient air. Changes in expression of selected genes were confirmed with real-time reverse transcriptase polymerase chain reaction. Left ventricular cardiomyocytes were isolated from adult animals in both groups, and cellular morphology and viability were compared.


RESULTS
Microarray analyses revealed significant changes in 1945 and 422 genes in neonates and adults, respectively. Changes in genes associated with adaptive vascular remodeling and energy homeostasis, as well as regulation of apoptosis, were confirmed by real-time reverse transcriptase polymerase chain reaction. The viability of cardiomyocytes isolated from hypoxic animals was significantly lower than in those from control animals (36.7% +/- 13.3% vs 85.0% +/- 2.9%, P = .024).


CONCLUSIONS
Neonatal hypoxia is associated with significant changes in left ventricular gene expression in both neonatal and adult rats. This may have physiologic implications for the adult myocardium.
Del Duca
Danny
D
Division of Cardiovascular Surgery, Montréal Children's Hospital-McGill University Health Centre, Montréal, Québec, Canada.
Wong
Guoruey
G
Trieu
Phan
P
Rodaros
Demetra
D
Kouremenos
Athanasios
A
Tadevosyan
Artavazd
A
Vaniotis
George
G
Villeneuve
Louis R
LR
Tchervenkov
Christo I
CI
Nattel
Stanley
S
Allen
Bruce G
BG
Hébert
Terence E
TE
Rohlicek
Charles V
CV
D000222:Adaptation, Physiological; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins; D001238:Asphyxia Neonatorum / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D020869:Gene Expression Profiling; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
C528241:ANGPTL4 protein, rat; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007527:Isoenzymes; C497763:Notch1 protein, rat; C490443:Pea15 protein, rat; D010750:Phosphoproteins; D051881:Receptor, Notch1; C495694:Slc2a4 protein, rat; D025521:Tumor Suppressor Proteins; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase; D019704:Protein Disulfide-Isomerases