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阿司匹林触发的消退素D1通过环磷酸腺苷/蛋白激酶A（cAMP/PKA）途径减弱血小板衍生生长因子诱导的血管平滑肌细胞迁移。

Aspirin-triggered resolvin D1 attenuates PDGF-induced vascular smooth muscle cell migration via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway.

作者信息

Mottola Giorgio, Chatterjee Anuran, Wu Bian, Chen Mian, Conte Michael S

机构信息

Department of Surgery, Division of Vascular and Endovascular Surgery, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.

出版信息

PLoS One. 2017 Mar 31;12(3):e0174936. doi: 10.1371/journal.pone.0174936. eCollection 2017.

DOI:10.1371/journal.pone.0174936
PMID:28362840
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5376330/
Abstract

BACKGROUND AND OBJECTIVES

Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been previously shown to attenuate vascular smooth muscle cell (VSMC) migration, a key process in the development of intimal hyperplasia. We sought to investigate the role of the cAMP/PKA pathway in mediating the effects of the aspirin-triggered epimer 17R-RvD1 (AT-RvD1) on VSMC migration.

METHODS

VSMCs were harvested from human saphenous veins. VSMCs were analyzed for intracellular cAMP levels and PKA activity after exposure to AT-RvD1. Platelet-derived growth factor (PDGF)-induced migration and cytoskeletal changes in VSMCs were observed through scratch, Transwell, and cell shape assays in the presence or absence of a PKA inhibitor (Rp-8-Br-cAMP). Further investigation of the pathways involved in AT-RvD1 signaling was performed by measuring Rac1 activity, vasodilator stimulated phosphoprotein (VASP) phosphorylation and paxillin translocation. Finally, we examined the role of RvD1 receptors (GPR32 and ALX/FPR2) in AT-RvD1 induced effects on VSMC migration and PKA activity.

RESULTS

Treatment with AT-RvD1 induced a significant increase in cAMP levels and PKA activity in VSMCs at 5 minutes and 30 minutes, respectively. AT-RvD1 attenuated PDGF-induced VSMC migration and cytoskeletal rearrangements. These effects were attenuated by the PKA inhibitor Rp-8-Br-cAMP, suggesting cAMP/PKA involvement. Treatment of VSMC with AT-RvD1 inhibited PDGF-stimulated Rac1 activity, increased VASP phosphorylation, and attenuated paxillin localization to focal adhesions; these effects were negated by the addition of Rp-8-Br-cAMP. The effects of AT-RvD1 on VSMC migration and PKA activity were attenuated by blocking ALX/FPR2, suggesting an important role of this G-protein coupled receptor.

CONCLUSIONS

Our results suggest that AT-RvD1 attenuates PDGF-induced VSMC migration via ALX/FPR2 and cAMP/PKA. Interference with Rac1, VASP and paxillin function appear to mediate the downstream effects of AT-RvD1 on VSMC migration.

摘要

背景与目的

消退素D1（RvD1）是一种特殊的促消退脂质介质，此前已证明其可减弱血管平滑肌细胞（VSMC）迁移，这是内膜增生发展过程中的关键环节。我们旨在研究环磷酸腺苷/蛋白激酶A（cAMP/PKA）信号通路在介导阿司匹林触发的差向异构体17R-RvD1（AT-RvD1）对VSMC迁移作用中的角色。

方法

从人隐静脉中获取VSMC。VSMC在暴露于AT-RvD1后，分析其细胞内cAMP水平和PKA活性。通过划痕实验、Transwell实验以及细胞形态实验，在有或无PKA抑制剂（Rp-8-Br-cAMP）的情况下，观察血小板衍生生长因子（PDGF）诱导的VSMC迁移和细胞骨架变化。通过测量Rac1活性、血管舒张刺激磷蛋白（VASP）磷酸化和桩蛋白转位，进一步研究AT-RvD1信号传导涉及的信号通路。最后，我们研究了RvD1受体（GPR32和ALX/FPR2）在AT-RvD1诱导的对VSMC迁移和PKA活性影响中的作用。

结果

用AT-RvD1处理分别在5分钟和30分钟时使VSMC中的cAMP水平和PKA活性显著增加。AT-RvD1减弱了PDGF诱导的VSMC迁移和细胞骨架重排。PKA抑制剂Rp-8-Br-cAMP减弱了这些作用，提示cAMP/PKA参与其中。用AT-RvD1处理VSMC抑制了PDGF刺激的Rac1活性，增加了VASP磷酸化，并减弱了桩蛋白在粘着斑的定位；添加Rp-8-Br-cAMP使这些作用消失。通过阻断ALX/FPR2减弱了AT-RvD1对VSMC迁移和PKA活性的作用，提示该G蛋白偶联受体的重要作用。

结论

我们的结果表明，AT-RvD1通过ALX/FPR2和cAMP/PKA减弱PDGF诱导的VSMC迁移。对Rac1、VASP和桩蛋白功能的干扰似乎介导了AT-RvD1对VSMC迁移的下游作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f4d/5376330/90a2037c5296/pone.0174936.g009.jpg
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