Perlecan deficiency causes endothelial dysfunction by reducing the expression of endothelial nitric oxide synthase.
Perlecan deficiency causes endothelial dysfunction by reducing the expression of endothelial nitric oxide synthase.
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DOI：
10.14814/phy2.12272
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发表时间：
2015-01-01
影响因子：
2.5
通讯作者：
Arikawa-Hirasawa E
中科院分区：
文献类型：
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作者：
Nonaka R;Iesaki T;de Vega S;Daida H;Okada T;Sasaki T;Arikawa-Hirasawa E
串珠素是一种主要的硫酸乙酰肝素蛋白聚糖，存在于血管壁的内皮下细胞外基质中。本研究的目的是探讨串珠素在血管张力调节中的作用。使用先前开发的条件性串珠蛋白聚糖缺陷小鼠模型测量离体主动脉环的等长力变化。血管先用苯肾上腺素预收缩，然后用浓度增加的血管舒张药处理。由乙酰胆碱引起的内皮依赖性舒张在串珠素缺陷型血管中显著降低，而由外源性一氧化氮供体硝普钠引起的内皮非依赖性舒张保持良好。通过真实的时间聚合酶链反应检测到的内皮型一氧化氮合酶（eNOS）基因的表达在串珠素缺陷型乳腺癌中显著降低。使用Western印迹检测的eNOS蛋白的表达在串珠素缺陷型乳腺癌中也显著降低。我们研究了串珠素在eNOS基因表达中的作用，通过使用串珠素的小干扰RNA（siRNA）建立串珠素敲低的人主动脉内皮细胞。串珠素siRNA处理的细胞中串珠素基因表达显著降低，导致eNOS基因表达显著降低。串珠素缺乏诱导内皮功能障碍，如内皮依赖性舒张的减少所示，至少部分是由于eNOS表达的减少。这些发现表明串珠素在正常生长过程中激活eNOS基因表达中起作用。串珠素缺乏至少部分诱导内皮功能障碍，eNOS表达减少。这些发现表明串珠素在正常生长过程中激活eNOS表达中起作用。
Perlecan is a major heparan sulfate proteoglycan found in the subendothelial extracellular matrix of the vascular wall. The aim of this study was to investigate the role of perlecan in the regulation of vascular tone. A previously developed conditional perlecan‐deficient mouse model was used to measure changes in the isometric force of isolated aortic rings. The vessels were first precontracted with phenylephrine, and then treated with increasing concentrations of vasorelaxants. Endothelium‐dependent relaxation, elicited by acetylcholine, was significantly reduced in the perlecan‐deficient aortas, whereas endothelium‐independent relaxation caused by the exogenous nitric oxide donor sodium nitroprusside remained well preserved. The expression of the endothelial nitric oxide synthase (eNOS) gene, detected by real‐time polymerase chain reaction, was significantly decreased in the perlecan‐deficient aortas. The expression of eNOS protein detected using Western blotting was also significantly decreased in the perlecan‐deficient aortas. We examined the role of perlecan in eNOS gene expression by creating perlecan knockdown human aortic endothelial cells using small interfering RNA (siRNA) for perlecan. Perlecan gene expression was significantly reduced in the perlecan siRNA‐treated cells, resulting in a significant decrease in eNOS gene expression. Perlecan deficiency induced endothelial dysfunction, as indicated by a reduction in endothelium‐dependent relaxation due, at least partly, to a reduction in eNOS expression. These findings suggest that perlecan plays a role in the activation of eNOS gene expression during normal growth processes. Perlecan deficiency induced endothelial dysfunction at least partly, to a reduction in eNOS expression. These findings suggest that perlecan plays a role in the activation of the eNOS expression during normal growth processes.