DNA microarray analysis for human congenital heart disease
DNA microarray analysis for human congenital heart disease
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DOI：
10.1385/cbb:44:1:001
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发表时间：
2006-01-01
影响因子：
2.6
通讯作者：
Bogers, AJJC
中科院分区：
文献类型：
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作者：
Sharma, HS;Peters, THE;Bogers, AJJC
右室肥大和功能衰竭是青紫型先天性心脏病、法洛四联症(TF)的显著特征。患有TF的患者在非常年轻的时候就需要进行初次心脏手术。为了深入了解右室肥厚的潜在分子机制，并找出与转铁蛋白相关的基因(S)，采用基于表达谱的微阵列技术对接受一期矫治的年轻转铁性心动过速患者的右室活检组织进行差异基因表达谱分析。应用免疫组织化学定量方法检测血管内皮生长因子(VEGF)、Flk-1和细胞外基质(ECM)蛋白(胶原蛋白和纤维连接蛋白)在TF患者心肌组织中的表达及血管计数和心肌细胞大小。在236个表达模式改变的基因中，VEGF(1.8倍)和ECM标志物明显上调(FN，2.4倍；I型胶原，7.5倍；III型胶原，4.4倍)，Flk-1和大多数基质金属蛋白酶(MMPs)没有变化，但MMP-13和-17水平下降。金属蛋白酶组织抑制物呈下调模式。心肌细胞和间质及血管周围区ECM蛋白(纤维连接蛋白、I型和III型胶原)的染色在TF患者中增加(p<；0.01)。形态计量学分析显示，TF-1患者血管密度增加(p<；0.05)，壁厚不变，心肌细胞横截面积增大(p<；0.01)，且与年龄呈线性相关(p<；0.01)。我们的结论是，编码血管内皮生长因子和细胞外基质蛋白的基因上调是导致TE患者右室肥厚和血管生成受阻的关键事件。
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 immunohistochemistry, 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 I alpha, 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 TE