Extracellular ubiquitin modulates cardiac fibroblast phenotype and function via its interaction with CXCR4.
Extracellular ubiquitin modulates cardiac fibroblast phenotype and function via its interaction with CXCR4.
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DOI：
10.1016/j.lfs.2018.09.012
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发表时间：
2018-10-15
期刊：
影响因子：
6.1
通讯作者：
Singh K
中科院分区：
文献类型：
--
作者：
Scofield SLC;Daniels CR;Dalal S;Millard JA;Singh M;Singh K
β-肾上腺素能受体（β-AR）刺激可增加细胞外泛素（UB）水平，外源性UB在β-AR刺激的心肌重塑中起重要作用，影响心功能、纤维化和心肌细胞凋亡。心脏成纤维细胞对于维持心脏的正常功能以及响应于损伤的心脏结构重塑至关重要。我们假设细胞外UB通过与CXC趋化因子受体4（CXCR4）的相互作用调节心脏成纤维细胞的表型和功能。使用血清饥饿的成年心脏成纤维细胞来鉴定CXCR4作为UB的受体。通过荧光显微镜、免疫共沉淀、蛋白质印迹、增殖、迁移和胶原收缩试验，研究UB/CXCR4轴对细胞信号传导的作用，以及成纤维细胞表型和功能的调节。使用荧光显微镜和免疫共沉淀试验，我们提供的证据表明，细胞外UB与CXCR4相互作用。CXCR4拮抗剂AMD 3100可抑制UB与CXCR4的相互作用。UB激活ERK 1/2，而非Akt。增强VEGF-A表达，同时降低β 3整合素表达。两种突变的UB蛋白（V70A和F4A;不能与CXCR4相互作用）未能影响VEGF-A和β 3整合素的表达。UB处理抑制细胞向伤口中的迁移和FBS刺激的细胞增殖。UB增强α-平滑肌肌动蛋白（肌成纤维细胞分化的标志物）的表达和成纤维细胞填充的胶原凝胶垫的收缩。UB的大部分作用被AMD 3100抵消。本文提供的数据表明UB与CXCR4相互作用，UB/CXCR4相互作用影响细胞内信号传导，并调节成纤维细胞表型和功能。
β-adrenergic receptor (β-AR) stimulation increases extracellular levels of ubiquitin (UB), and exogenous UB plays an important role in β-AR-stimulated myocardial remodeling with effects on heart function, fibrosis and myocyte apoptosis. Cardiac fibroblasts are vital for maintaining the normal function of the heart, and in the structural remodeling of the heart in response to injury. Here we hypothesized that extracellular UB modulates cardiac fibroblast phenotype and function via its interaction with CXC chemokine receptor type 4 (CXCR4). Serum starved adult cardiac fibroblasts were used to identify CXCR4 as a receptor for UB. Fluorescent microscopy, co-immunoprecipitation, western blot, proliferation, migration and collagen contraction assays were performed to investigate the role of UB/CXCR4 axis on cell signaling, and modulation of fibroblast phenotype and function. Using fluorescent microscopy and co-immunoprecipitation assay, we provide evidence that extracellular UB interacts with CXCR4. CXCR4 antagonist, AMD3100, inhibited interaction of UB with CXCR4. UB activated ERK1/2, not Akt. It enhanced VEGF-A expression, while decreasing β3 integrins expression. Two mutated UB proteins (V70A and F4A; unable to interact with CXCR4) failed to affect the expression of VEGF-A and β3 integrins. UB treatment inhibited migration of cells into the wound and FBS-stimulated cell proliferation. UB enhanced expression of α-smooth muscle actin (marker of myofibroblast differentiation) and contraction of fibroblast-populated collagen gel pads. Most of the effects of UB were negated by AMD3100. The data presented here suggest that UB interacts with CXCR4, and UB/CXCR4 interaction affects intracellular signaling, and modulates fibroblast phenotype and function.
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影响因子：
3.7
作者：
Balasubramanian S;Quinones L;Kasiganesan H;Zhang Y;Pleasant DL;Sundararaj KP;Zile MR;Bradshaw AD;Kuppuswamy D
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影响因子：
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DOI：
10.1016/j.bbamcr.2012.08.023
发表时间：
2013-04
影响因子：
5.1
作者：
Chen, Wei;Frangogiannis, Nikolaos G.
通讯作者：
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影响因子：
4.8
作者：
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