Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice.
Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice.
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Caveolin-1 支架结构域肽通过抑制小鼠中 TGF-β1/Smad 信号传导减轻肝纤维化
DOI：
10.3390/ijms19061729
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发表时间：
2018-06-11
影响因子：
5.6
通讯作者：
Sun Q
中科院分区：
文献类型：
--
作者：
Lu J;Zhang J;Wang Y;Sun Q
肝纤维化是以肝星状细胞(HSCs)活化和细胞外基质(ECM)过度生成为特征的常见病理过程。小窝蛋白1是小窝的主要成分，被认为是包括转化生长因子β1信号在内的多种信号分子的重要抑制因子。为探讨Cav1在肝纤维化中的作用，对Cav1基因缺陷(Cav1−/−)小鼠和野生型(WT)小鼠进行了四氯化碳(CCl4)诱导的肝纤维化模型。结果显示，Cav1CCl4处理前−/−小鼠和WT小鼠在炎症反应和胶原含量方面没有显著差异。在给予CCl_4后，Cav1−/−小鼠表现出增强的转化生长因子-Smad1信号，这反映在Smad2的磷酸化和肝脏中的胶原沉积明显多于WT动物。定性和定量分析表明，肝脏炎性损伤明显加重，并伴有肝细胞变性和坏死增加，丙氨酸氨基转移酶/天冬氨酸氨基转移酶、转化生长因子-α和IL-1β水平升高。α-平滑肌肌动蛋白(α-SMA)、胶原α1(I)和胶原α1(III)的基因和蛋白水平在Cav1−/−动物中进一步增强。我们还观察到给予Cav1支架结构域肽(Csd)的Cav1、−/−和WT动物的胶原含量显著降低。体外研究表明，肝星状细胞Smad2的磷酸化受到抑制，并伴有α-SMA、胶原α1(I)和α1(III)的蛋白水平下降。结论：Cav1是转化生长因子-β-1/Smad信号转导通路的重要抑制因子，参与肝干细胞活化和胶原合成，有望成为治疗肝纤维化的靶点。
Liver fibrosis is the common pathological process characterized by activation of hepatic stellate cells (HSCs) and overproduction of extracellular matrix (ECM). Caveolin-1 (Cav1), the principal component of caveolae, is regarded as an important inhibitor of multiple signaling molecules including transforming growth factor β1(TGF-β1) signaling. To evaluate the role of Cav1 in liver fibrosis, Cav1 deficient (Cav1−/−) and wild type (WT) mice were subjected to liver fibrosis induced by carbon tetrachloride (CCl4). Results indicated no significant difference between Cav1−/− and WT mice in inflammation or collagen content before CCl4 treatment. After CCl4 administration, Cav1−/− mice showed enhanced TGF-β1 signaling, as reflected by a significantly greater amount of phosphorylation of Smad2 and collagen deposition in livers over WT animals. Qualitative and quantitative analysis indicated that inflammatory injury to the liver was markedly aggravated, accompanied by increased degeneration and necrosis of hepatocytes, higher alanine aminotransferase (ALT)/aspartate aminotransferase (AST), TGF-α and IL-1β levels in Cav1−/− animals. The mRNA and protein levels of α-smooth muscle actin (α-SMA), Collagen α1(I), and Collagen α1(III) were further enhanced in Cav1−/− animals. We also observed a significant decrease in collagen content in Cav1−/− and WT animals administrated with Cav1 scaffolding domain peptides (CSD). In vitro study indicated that phosphorylation of Smad2 was inhibited after CSD treatment, accompanied by decreased protein levels of α-SMA, Collagen α1(I), and Collagen α1(III) in HSCs. We conclude that Cav1 is an important inhibitor of TGF-β1/Smad signaling in HSCs activation and collagen production, which might make it a promising target for therapy of liver fibrosis.
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影响因子：
5
作者：
Harvey RD;Calaghan SC
通讯作者：
Calaghan SC
影响因子：
3.7
作者：
Byrne DP;Dart C;Rigden DJ
通讯作者：
Rigden DJ
DOI：
10.1073/pnas.0407224102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Bernatchez, PN;Bauer, PM;Sessa, WC
通讯作者：
Sessa, WC
影响因子：
82.9
作者：
Bucci, M;Gratton, JP;Sessa, WC
通讯作者：
Sessa, WC
影响因子：
20.1
作者：
Rybin, VO;Xu, XH;Steinberg, SF
通讯作者：
Steinberg, SF