Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery
Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery
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DOI：
10.1161/01.res.84.6.647
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发表时间：
1999-04-02
影响因子：
20.1
通讯作者：
Walsh, K
中科院分区：
文献类型：
--
作者：
Mano, T;Luo, ZY;Walsh, K
GATA-6 转录因子在培养的静止血管平滑肌细胞 (VSMC) 中表达，其转录物水平在有丝分裂原刺激下迅速下调。在这项研究中，我们证明了球囊损伤后大鼠颈动脉中 GATA-6 转录物、蛋白质和 DNA 结合活性的下调。损伤后 1 天和 3 天检测到下调，并在 7 天恢复。为了评估 GATA-6 下调在损伤诱导的血管病变形成中的作用，使用腺病毒载体表达野生型人 GATA-6 cDNA (Ad-GATA6) 或缺乏部分锌指结构域的失活突变 cDNA (Ad-GATA6 Delta ZF)。球囊损伤后，腺病毒介导的 GATA-6 基因转移至血管壁，部分恢复了 GATA-6 蛋白水平和 DNA 结合活性至损伤前的水平。局部递送 Ad-GATA6 而不是 Ad-GATA6 Delta ZF，相对于盐水对照抑制病变形成 46%，相对于表达 lacZ 的对照腺病毒抑制 50%。 Ad-GATA6的局部递送还逆转了与损伤诱导的VSMC表型调节相关的平滑肌肌球蛋白重链、平滑肌α-肌动蛋白、钙调蛋白、纽蛋白、亚纽蛋白和增殖细胞核抗原的表达模式的变化。这些数据表明损伤诱导的 GATA-6 下调是 VSMC 表型调节的一个基本特征，有助于血管病变的形成。
The GATA-6 transcription factor is expressed in quiescent vascular smooth muscle cells (VSMCs) in culture, and levels of its transcript are rapidly downregulated on mitogen stimulation. In this study, we demonstrate that the GATA-6 transcript, protein, and DNA-binding activity are downregulated in rat carotid arteries on balloon injury. Downregulation was detected at 1 and 3 days after injury and recovered by 7 days. To assess the role of GATA-6 downregulation in injury-induced vascular lesion formation, adenoviral vectors were used to express wild-type human GATA-6 cDNA (Ad-GATA6) or an inactive mutant cDNA that lacks a portion of the zinc-finger domain (Ad-GATA6 Delta ZF). Adenovirus-mediated GATA-6 gene transfer to the vessel wall after balloon injury partially restored the levels of GATA-6 protein and DNA-binding activity to before injury levels, The local delivery of Ad-GATA6 but not Ad-GATA6 Delta ZF inhibited lesion formation by 46% relative to saline control and 50% relative to a control adenovirus that expressed lacZ. Local delivery of Ad-GATA6 also reversed changes in the expression patterns of smooth muscle myosin heavy chain, smooth muscle alpha-actin, calponin, vinculin, metavinculin, and proliferating cell nuclear antigen that are associated with injury-induced VSMC phenotypic modulation. These data indicate that the injury-induced downregulation of GATA-6 is an essential feature of VSMC phenotypic modulation that contributes to vessel lesion formation.