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Neonatal Hypoxia is Associated with Lasting Changes in Left Ventricular Gene Expression: An Animal Model
D. Del Duca1, G. Wong2, A. Kouremenos3, C. I. Tchervenkov1, C. V. Rohlicek4, T. E. Hébert3. 1Division of Cardiovascular Surgery, Montreal Children's Hospital, Montreal, QC, Canada, 2Department of Physiology, McGill University, Montreal, QC, Canada, 3Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada, 4Division of Cardiology, Montreal Children's Hospital, Montreal, QC, Canada,
BACKGROUND:
Innovations in pediatric cardiac surgery have resulted in significant improvements in survival for children with congenital heart disease (CHD). However, the risk of complications and mortality after surgery in adults with CHD remains high, and the reasons for this are unclear. We hypothesize that neonatal hypoxia causes lasting changes in gene expression in the developing heart, altering cardiac structure and function in the adult.
METHODS:
Genome-wide DNA microarray expression analyses were performed using left ventricular free wall tissue obtained from two groups of male Sprague Dawley rats: a) rats exposed to hypoxia (FiO2 = 0.12) for days 1 to 10 of life and subsequently reared in ambient air, and b) rats reared only in ambient air with no exposure to hypoxia. Analyses were performed immediately following the hypoxic stress (day 10) and in the adult animals (day 90).
RESULTS:
Analyses from both neonatal and adult animals following neonatal hypoxia, using an unpaired t-test and robust multiarray analysis, revealed more than 900 genes whose expression was significantly changed (p < 0.05) with a two-fold upregulation or downregulation. While the global pattern of changes was relatively small at day 10, there were dramatic changes in gene expression evident in the adult animals. We observed significant upregulation of the hypoxia-induced transcription factor HIF-1α and its auxiliary subunit HIF-1β, as well as changes in a number of downstream protein targets such as VEGF, CITED2, Pitx2 and the α1B-adrenergic receptor in the adult animals. Both MEF2d and MyoD, two key transcription factors associated with muscle development and maintenance, were downregulated in the neonatal animals, and these latter changes were more marked in the adult animals. MyoG, a transcription factor involved in terminal muscle differentiation, was also upregulated. Significant changes were found in gene families associated with other aspects of cellular signalling, including the MAP kinase pathway, and the tyrosine kinase networks involved in metabolic control.
CONCLUSIONS:
Neonatal hypoxia is associated with lasting changes in left ventricular gene expression in the adult rat. These changes involve a large number of genes associated with diverse aspects of cellular regulation. Understanding how this may be related to altered cellular function has important implications in regards to basic cardiac development, and in the innovation of prognostic algorithms and treatment approaches for adults with CHD.
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