Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts
Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts
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DOI：
10.1091/mbc.e03-12-0902
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发表时间：
2004-06-01
影响因子：
3.3
通讯作者：
Abraham, DJ
中科院分区：
文献类型：
--
作者：
Xu, SW;Chen, YL;Abraham, DJ
内皮素是内皮衍生肽家族，具有多种功能，包括血管收缩。内皮素-1（ET-1）在组织修复过程中上调，并促进肌成纤维细胞收缩和迁移，因此有助于组织修复过程中的基质重塑。在这里，我们表明，除了ET-1正常肺成纤维细胞诱导蛋白质的表达，有助于收缩表型，包括α-平滑肌肌动蛋白（α-SMA），埃兹蛋白，膜突蛋白，桩蛋白。我们证实，ET-1增强肺成纤维细胞收缩细胞外基质的能力，这是组织修复所必需的功能，通过诱导从头蛋白质合成。用LY 294002和渥曼青霉素阻断Akt/磷酸肌醇3-激酶（PI 3-激酶）通路可阻止ET-1诱导α-SMA、埃兹蛋白、桩蛋白和膜突蛋白以及促进基质收缩的能力。显性负性rac和Akt阻断ET-1促进α-SMA应力纤维形成的能力。使用特定的ET-1受体抑制剂，我们表明，ET-1诱导胶原基质收缩通过ETA，但不是ETB，受体。相对于正常的肺成纤维细胞，从患有纤维化疾病系统性硬化症（硬皮病）的患者的瘢痕培养的成纤维细胞显示增强的ET-1表达和结合。系统性硬化症肺成纤维细胞显示出增加的收缩胶原基质的能力和升高的促收缩蛋白α-SMA、埃兹蛋白、桩蛋白和膜突蛋白的表达，其通过拮抗内源性ET-1信号传导而大大降低。因此，阻断ET-1或PI 3-激酶/Akt级联反应可能有利于减少肺纤维化中的瘢痕形成。
The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including alpha-smooth muscle actin (alpha-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of alpha-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins alpha-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis.