Atorvastatin's Therapeutic Potential in Atherosclerosis: Inhibiting TGF-β-Induced Proteoglycan Glycosaminoglycan Chain Elongation through ROS-ERK1/2-Smad2L Signaling Pathway Modulation in Vascular Smooth Muscle Cells.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-02-01 DOI:10.22074/cellj.2023.2010482.1397

Hossein Ghaderi-Zefrehi, Ghorban Mohammadzadeh, Mojtaba Rashidi, Maryam Adelipour, Hossein Babaahmadi Rezaei

{"title":"Atorvastatin's Therapeutic Potential in Atherosclerosis: Inhibiting TGF-β-Induced Proteoglycan Glycosaminoglycan Chain Elongation through ROS-ERK1/2-Smad2L Signaling Pathway Modulation in Vascular Smooth Muscle Cells.","authors":"Hossein Ghaderi-Zefrehi, Ghorban Mohammadzadeh, Mojtaba Rashidi, Maryam Adelipour, Hossein Babaahmadi Rezaei","doi":"10.22074/cellj.2023.2010482.1397","DOIUrl":null,"url":null,"abstract":"Objective: According to the response-to-retention hypothesis, the inception of atherosclerosis is attributed to the deposition and retention of lipoprotein in the arterial intima, facilitated by altered proteoglycans with hyperelongated glycosaminoglycan (GAG) chains. Recent studies have elucidated a signaling pathway whereby transforming growth factor-β (TGF-β) promotes the expression of genes linked to proteoglycan GAG chain elongation (CHSY1 and CHST11) via reactive oxygen species (ROS) and the downstream phosphorylation of ERK1/2 and Smad2L. Atorvastatin is known to exhibit pleiotropic effects, including antioxidant and anti-inflammatory. The purpose of the present research was to ascertain the influence of atorvastatin on TGF-β-stimulated expression of CHSY1 and CHST11 and associated signaling pathways using an in vitro model.Materials and methods: In this experimental study, vascular smooth muscle cells (VSMCs) were pre-incubated with atorvastatin (0.1-10 μM) prior to being stimulated with TGF-β (2 ng/ml). The experiment aimed to evaluate the phosphorylation levels of Smad2C, Smad2L, ERK1/2, the NOX p47phox subunit, ROS production, and the mRNA expression of CHST11 and CHSY1.Results: Our research results indicated that atorvastatin inhibited TGF-β-stimulated CHSY1 and CHST11 mRNA expression. Further experiments showed that atorvastatin diminished TGF-β-stimulated ROS production and weakened TGF-β-stimulated phosphorylation of p47phox, ERK1/2, and Smad2L; however, we observed no effect on the TGF-β- Smad2C pathway.Conclusion: These data suggest that atorvastatin demonstrates anti-atherogenic properties through the modulation of the ROS-ERK1/2-Smad2L signaling pathway. This provides valuable insight into the potential mechanisms by which atorvastatin exerts its pleiotropic effects against atherosclerosis.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":null,"pages":null},"PeriodicalIF":16.4000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10924836/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.22074/cellj.2023.2010482.1397","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: According to the response-to-retention hypothesis, the inception of atherosclerosis is attributed to the deposition and retention of lipoprotein in the arterial intima, facilitated by altered proteoglycans with hyperelongated glycosaminoglycan (GAG) chains. Recent studies have elucidated a signaling pathway whereby transforming growth factor-β (TGF-β) promotes the expression of genes linked to proteoglycan GAG chain elongation (CHSY1 and CHST11) via reactive oxygen species (ROS) and the downstream phosphorylation of ERK1/2 and Smad2L. Atorvastatin is known to exhibit pleiotropic effects, including antioxidant and anti-inflammatory. The purpose of the present research was to ascertain the influence of atorvastatin on TGF-β-stimulated expression of CHSY1 and CHST11 and associated signaling pathways using an in vitro model.

Materials and methods: In this experimental study, vascular smooth muscle cells (VSMCs) were pre-incubated with atorvastatin (0.1-10 μM) prior to being stimulated with TGF-β (2 ng/ml). The experiment aimed to evaluate the phosphorylation levels of Smad2C, Smad2L, ERK1/2, the NOX p47phox subunit, ROS production, and the mRNA expression of CHST11 and CHSY1.

Results: Our research results indicated that atorvastatin inhibited TGF-β-stimulated CHSY1 and CHST11 mRNA expression. Further experiments showed that atorvastatin diminished TGF-β-stimulated ROS production and weakened TGF-β-stimulated phosphorylation of p47phox, ERK1/2, and Smad2L; however, we observed no effect on the TGF-β- Smad2C pathway.

Conclusion: These data suggest that atorvastatin demonstrates anti-atherogenic properties through the modulation of the ROS-ERK1/2-Smad2L signaling pathway. This provides valuable insight into the potential mechanisms by which atorvastatin exerts its pleiotropic effects against atherosclerosis.

查看原文本刊更多论文

阿托伐他汀在动脉粥样硬化中的治疗潜力：通过调节血管平滑肌细胞中的 ROS-ERK1/2-Smad2L 信号通路，抑制 TGF-β 诱导的蛋白多糖氨基多糖链延长。

目的：根据 "反应-滞留 "假说，动脉粥样硬化的起因是脂蛋白在动脉内膜的沉积和滞留，而具有超长糖胺聚糖（GAG）链的蛋白聚糖的改变促进了脂蛋白的沉积和滞留。最近的研究阐明了一种信号通路，即转化生长因子-β（TGF-β）通过活性氧（ROS）和下游的 ERK1/2 和 Smad2L 磷酸化促进与蛋白聚糖 GAG 链伸长有关的基因（CHSY1 和 CHST11）的表达。众所周知，阿托伐他汀具有多种效应，包括抗氧化和抗炎。本研究的目的是利用体外模型确定阿托伐他汀对 TGF-β 刺激的 CHSY1 和 CHST11 表达及相关信号通路的影响：在本实验研究中，血管平滑肌细胞（VSMCs）在接受 TGF-β （2 ng/ml）刺激前与阿托伐他汀（0.1-10 μM）预孵育。实验旨在评估 Smad2C、Smad2L、ERK1/2、NOX p47phox 亚基的磷酸化水平、ROS 的产生以及 CHST11 和 CHSY1 的 mRNA 表达：我们的研究结果表明，阿托伐他汀抑制了 TGF-β 刺激的 CHSY1 和 CHST11 mRNA 的表达。进一步的实验表明，阿托伐他汀减少了TGF-β刺激的ROS产生，削弱了TGF-β刺激的p47phox、ERK1/2和Smad2L的磷酸化；然而，我们没有观察到对TGF-β- Smad2C通路的影响：这些数据表明，阿托伐他汀通过调节 ROS-ERK1/2-Smad2L 信号通路具有抗动脉粥样硬化的特性。这些数据表明，阿托伐他汀通过调节ROS-ERK1/2-Smad2L信号通路具有抗动脉粥样硬化的特性，这为深入了解阿托伐他汀发挥抗动脉粥样硬化多重效应的潜在机制提供了宝贵的信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.