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DNA microarray analysis for human congenital heart disease.

Hari S Sharma·Theodorus H F Peters·Michael J Moorhouse·Peter J van der Spek·Ad J J C Bogers
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Abstract

Right ventricular hypertrophy and failure are prominent features in cyanotic congenital heart disease, tetralogy of Fallot (TF). Patients with TF require primary cardiac surgery at a very young age. To gain insight into the underlying molecular mechanisms of right ventricular hypertrophy and to identify gene(s) involved in TF, differential gene expression profile was assessed using expression-based microarray technology on right ventricular biopsies from young TF patients who underwent primary correction. By using quantitative immuno histochemistry, expression of vascular endothelial growth factor (VEGF), flk-1, and extracellular matrix (ECM) proteins (collagens and fibronectin) as well as vessel counts and myocyte cell size was evaluated in TF patients in relation to age-matched controls. Among 236 genes showing altered expression pattern in TF patients, VEGF (1.8-fold) and ECM markers were clearly upregulated (fibronectin, 2.4-fold; collagen Ialpha, 7.5-fold; and collagen III, 4.4-fold); flk-1 and most matrix metalloproteinases (MMPs) remained unchanged, except the levels of MMP-13 and -17 declined. Tissue inhibitors of metalloproteinases showed a downregulated pattern. Staining of VEGF in cardiomyocytes and of ECM proteins (fibronectin, collagen I and III) in interstitial as well as in perivascular area was increased (p < 0.01) in TF patients. Morphometric analysis revealed enhanced vascular density (p < 0.05) with unchanged wall thickness and enlarged myocyte cross-sectional areas (p < 0.01) with linear correlation (p < 0.01) with the age in TF-1 patients. We conclude that the upregulation of genes encoding VEGF and ECM proteins are the key events contributing to right ventricular hypertrophy and stunted angiogenesis in patients with TF.

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AdultCardiovascular DiseasesComputational BiologyDown-RegulationEndomyocardial FibrosisExtracellular Matrix ProteinsGene ExpressionGene Expression ProfilingGenomicsHeart Defects, CongenitalHumansHypertrophy, Right VentricularInfantMyocytes, CardiacOligonucleotide Array Sequence AnalysisTetralogy of FallotUp-RegulationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Journal ArticleResearch Support, Non-U.S. Gov't

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Hari S Sharma, Theodorus H F Peters, Michael J Moorhouse, Peter J van der Spek, Ad J J C Bogers. 2006. DNA microarray analysis for human congenital heart disease.. https://doi.org/10.1385/cbb%3A44%3A1%3A001

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