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β1 肾上腺素能受体拮抗剂美托洛尔对高糖处理的人微血管视网膜内皮细胞的抗炎作用。

The Anti-Inflammatory Effect of the β1-Adrenergic Receptor Antagonist Metoprolol on High Glucose Treated Human Microvascular Retinal Endothelial Cells.

机构信息

Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy.

U.O. Clinical Pathology, Department of Hematology, AUSL Romagna, 47522 Cesena, Italy.

出版信息

Cells. 2021 Dec 24;11(1):51. doi: 10.3390/cells11010051.

DOI:10.3390/cells11010051
PMID:35011613
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8750370/
Abstract

Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.

摘要

高血糖引起的血视网膜屏障损伤是糖尿病视网膜病变的主要病理事件，它是由细胞对活性氧（ROS）积累的反应减少和炎症增加引起的。本研究的目的是评估选择性β1-肾上腺素能受体（β1-AR）拮抗剂美托洛尔是否能调节高血糖条件下的炎症反应。为此，将人视网膜内皮细胞（HREC）用正常（5 mM）或高葡萄糖（25 mM，HG）处理，同时存在美托洛尔（10 μM）、肾上腺素（1 μM）或这两种化合物。美托洛尔可防止 HG 诱导的细胞活力降低（MTT 测定）和 HREC 血管生成潜力的调节（管形成测定），降低 TNF-α、IL-1β 和 VEGF mRNA 水平（qRT-PCR）。此外，美托洛尔可防止磷酸化 ERK1/2、磷酸化 cPLA、COX2 和蛋白水平（Western blot）的增加，并拮抗 ERK1/2 和 cPLA 的易位（高内涵筛选）。美托洛尔通过激活 Keap1/Nrf2/HO-1 通路介导的抗氧化细胞反应，减少 HG 刺激的 HREC 中 ROS 的积累。总之，美托洛尔对 HG 刺激的 HREC 有双重作用，可降低促炎 ERK1/2/cPLA/COX2 轴的激活，并通过激活 Keap1/Nrf2/HO-1 通路来拮抗 ROS 的积累。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/6afae01aa8b5/cells-11-00051-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/3c9f1419c05b/cells-11-00051-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/d21eaf2e1ec8/cells-11-00051-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/8fab587fe739/cells-11-00051-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/8b6a438c3484/cells-11-00051-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/6afae01aa8b5/cells-11-00051-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/3c9f1419c05b/cells-11-00051-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/966fb6b1e6cc/cells-11-00051-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/7ab0f56f2be2/cells-11-00051-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/941cc03b52b8/cells-11-00051-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/d21eaf2e1ec8/cells-11-00051-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/8fab587fe739/cells-11-00051-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/8b6a438c3484/cells-11-00051-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7832/8750370/6afae01aa8b5/cells-11-00051-g008.jpg

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