Epac1 and PKA agonists inhibit ROS to reduce NLRP3 inflammasome proteins in retinal endothelial cells.

IF 1.8 3区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Vision Pub Date : 2022-01-01

Li Liu, Youde Jiang, Jena J Steinle

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Abstract

Purpose: Reactive oxygen species (ROS) activate inflammatory pathways in several organs, including the retina. More recent work has shown that ROS activate the NOD-like receptor protein 3 (NLRP3) inflammasome pathway proteins. We recently showed that the exchange protein activated by cAMP 1 (Epac1) and protein kinase A (PKA) regulates NLRP3 proteins in the retina. Our goal was to determine whether Epac1 and PKA reduce ROS and NLRP3 inflammasome proteins.

Methods: We used human primary retinal endothelial cells (RECs) grown in normal glucose (5 mM) and stimulated in normal glucose with hydrogen peroxide (H₂O₂) to induce ROS and measured NLRP3 pathway proteins. In some groups, we treated cells with an Epac1 or a PKA agonist in addition to H₂O₂ treatment to determine whether Epac1 and PKA reduced ROS and induced NLRP3 pathway proteins.

Results: The data showed that 500 µM H₂O₂ was the optimal dose to increase ROS in RECs. In RECs treated with H₂O₂, NLRP3 pathway proteins were increased, which were significantly reduced by cotreatment with PKA or Epac1 agonists. H₂O₂ significantly increased NIMA-related kinase 7 (Nek7) and purinergic 2X7 receptor 7 (P2X7) levels, which were blocked by Epac1 and PKA agonists.

Conclusions: Taken together, these data suggest that Epac1 and PKA reduce retinal inflammation through the reduced ROS-induced activation of NLRP3 pathway proteins.

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Epac1和PKA激动剂抑制ROS降低视网膜内皮细胞NLRP3炎性体蛋白。

目的:活性氧(ROS)激活包括视网膜在内的几个器官的炎症通路。最近的研究表明，ROS可激活nod样受体蛋白3 (NLRP3)炎性小体途径蛋白。我们最近发现，由cAMP 1 (Epac1)和蛋白激酶A (PKA)激活的交换蛋白调节视网膜中的NLRP3蛋白。我们的目的是确定Epac1和PKA是否减少ROS和NLRP3炎症小体蛋白。方法:用正常葡萄糖(5 mM)培养的人原代视网膜内皮细胞(RECs)，用过氧化氢(H2O2)刺激正常葡萄糖诱导ROS，并测定NLRP3通路蛋白。在一些组中，我们用Epac1或PKA激动剂除H2O2处理外处理细胞，以确定Epac1和PKA是否减少ROS并诱导NLRP3途径蛋白。结果:数据显示，500µM H2O2是增加RECs ROS的最佳剂量。在H2O2处理的RECs中，NLRP3通路蛋白增加，与PKA或Epac1激动剂共处理显著降低。H2O2显著增加了nima相关激酶7 (Nek7)和嘌呤能2X7受体7 (P2X7)的水平，这两种受体被Epac1和PKA激动剂阻断。结论:综上所述，这些数据表明Epac1和PKA通过减少ros诱导的NLRP3通路蛋白的激活来减轻视网膜炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Vision 生物-生化与分子生物学

CiteScore

4.40

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： Molecular Vision is a peer-reviewed journal dedicated to the dissemination of research results in molecular biology, cell biology, and the genetics of the visual system (ocular and cortical). Molecular Vision publishes articles presenting original research that has not previously been published and comprehensive articles reviewing the current status of a particular field or topic. Submissions to Molecular Vision are subjected to rigorous peer review. Molecular Vision does NOT publish preprints. For authors, Molecular Vision provides a rapid means of communicating important results. Access to Molecular Vision is free and unrestricted, allowing the widest possible audience for your article. Digital publishing allows you to use color images freely (and without fees). Additionally, you may publish animations, sounds, or other supplementary information that clarifies or supports your article. Each of the authors of an article may also list an electronic mail address (which will be updated upon request) to give interested readers easy access to authors.