Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts.
Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts.
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DOI：
10.1002/art.34336
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发表时间：
2012-06
影响因子：
--
通讯作者：
Koch, Alisa E.
中科院分区：
文献类型：
--
作者：
Tsou, Pei-Suen;Talia, Nadine N.;Pinney, Adam J.;Kendzicky, Ann;Piera-Velazquez, Sonsoles;Jimenez, Sergio A.;Seibold, James R.;Phillips, Kristine;Koch, Alisa E.
血小板源性生长因子 (PDGF) 及其受体 (PDGFR) 会促进硬皮病 (SSc) 真皮成纤维细胞的纤维化，从而产生过量的活性氧 (ROS)。 PDGFR 在 PDGF 刺激下被磷酸化，并被蛋白酪氨酸磷酸酶 (PTP)（包括 PTP1B）去磷酸化。在本研究中，我们确定硫醇敏感的 PTP1B 是否受到 ROS 的影响，从而增强 PDGFR 磷酸化 (p-PDGFR) 和胶原蛋白 I (Col I) 的合成。还研究了硫醇抗氧化剂 n-乙酰半胱氨酸 (NAC) 的作用。从皮肤中分离出成纤维细胞。磷酸盐释放测定用于 PTP1B 活性。与正常成纤维细胞相比，SSc 成纤维细胞中的 ROS 和 Col I 显着较高，同时游离硫醇含量显着较低。 PDGF刺激后，SSc成纤维细胞中不仅PDGFR和ERK1/2被更大程度地磷酸化，而且产生PTP1B的能力也受到阻碍。 SSc 成纤维细胞中 PTP1B 活性显着失活，这是由于较高水平的 ROS 导致半胱氨酸氧化所致，因为观察到包括 PTP1B 在内的多种 PTP 的氧化。正常成纤维细胞中 PTP1B 表达减少导致 Col I 增加。NAC 恢复了低 PTP1B 活性，改善了 p-PDGFR 的分布，减少了酪氨酸磷酸化蛋白和 Col I 的数量，并清除了 SSc 成纤维细胞中的 ROS。我们引入了一种新机制，ROS 通过 PTP1B 氧化失活导致显着的 PDGFR 激活，从而促进 SSc 成纤维细胞的促纤维化表型。我们的研究还提供了一种新的分子机制，NAC 疗法可以通过该机制作用于 ROS 和 PTP1B，从而使 SSc 患者受益。
Platelet-derived growth factor (PDGF) and its receptor (PDGFR) promote fibrosis in scleroderma (SSc) dermal fibroblasts, which produce excessive reactive oxygen species (ROS). PDGFR is phosphorylated upon PDGF stimulation, and dephosphorylated by protein tyrosine phosphatases (PTPs), including PTP1B. In this study we determine whether the thiol-sensitive PTP1B is affected by ROS, thus enhancing PDGFR phosphorylation (p-PDGFR) and collagen I (Col I) synthesis. The effect of a thiol antioxidant, n-acetylcysteine (NAC), was also investigated. Fibroblasts were isolated from skin. A phosphate release assay was used for PTP1B activity. ROS and Col I were significantly higher in SSc fibroblasts, accompanied by significantly lower amounts of free thiols compared to normal fibroblasts. After PDGF stimulation, not only were the PDGFR and ERK1/2 phosphorylated to a greater extent, but the ability to produce PTP1B was also hampered in SSc fibroblasts. PTP1B activity was significantly inactivated in SSc fibroblasts, which resulted from cysteine oxidation by higher levels of ROS, since oxidation of multiple PTPs, including PTP1B, was observed. Decreased PTP1B expression in normal fibroblasts led to increased Col I. NAC restored the low PTP1B activity, improved the profile of p-PDGFR, decreased the numbers of tyrosine-phosphorylated proteins and Col I, and scavenged ROS in SSc fibroblasts. We introduce a new mechanism by which ROS promote a profibrotic phenotype in SSc fibroblasts through oxidative inactivation of PTP1B leading to pronounced PDGFR activation. Our study also provides a novel molecular mechanism by which NAC therapy may act on ROS and PTP1B to benefit SSc patients.
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影响因子：
4.8
作者：
Kovalenko, M;Denner, K;Östman, A
通讯作者：
Östman, A
影响因子：
15.9
作者：
Kawaguchi, Y;Hara, M;Wright, TM
通讯作者：
Wright, TM
影响因子：
7.4
作者：
ARUOMA, OI;HALLIWELL, B;BUTLER, J
通讯作者：
BUTLER, J
DOI：
10.1161/01.atv.0000246777.30819.85
发表时间：
2006-12-01
影响因子：
8.7
作者：
Kappert, Kai;Sparwel, Jan;Ostman, Arne
通讯作者：
Ostman, Arne
影响因子：
4.3
作者：
Byon, JCH;Kusari, AB;Kusari, J
通讯作者：
Kusari, J