Shear-Sensitive circRNA-LONP2 Promotes Endothelial Inflammation and Atherosclerosis by Targeting NRF2/HO1 Signaling

IF 8.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Ruoyu Wang MM , Yue Zeng MM , Ziqi Chen PhD , Dongwei Ma MM , Xiaozhe Zhang PhD , Guifu Wu MD, PhD , Wendong Fan PhD
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引用次数: 0

Abstract

Hemodynamic shear stress is a frictional force that acts on vascular endothelial cells and is essential for endothelial homeostasis. Physiological laminar shear stress (LSS) suppresses endothelial inflammation and protects arteries from atherosclerosis. Herein, we screened differentially expressed circular RNAs (circRNAs) that were significantly altered in LSS-stimulated endothelial cells and found that circRNA-LONP2 was involved in modulating the flow-dependent inflammatory response. Furthermore, endothelial circRNA-LONP2 overexpression promoted endothelial inflammation and atherosclerosis in vitro and in vivo. Mechanistically, circRNA-LONP2 competitively sponged miR-200a-3p and subsequently promoted Kelch-like ECH-associated protein 1, Yes-associated protein 1, and enhancer of zeste homolog 2 expression, thereby inactivating nuclear factor erythroid 2–related factor 2/heme oxygenase-1 signaling, promoting oxidative stress and endothelial inflammation, and accelerating atherosclerosis. LSS-induced down-regulation of circRNA-LONP2 suppresses endothelial inflammation, at least in part, by activating the miR-200a-3p–mediated nuclear factor erythroid 2–related factor 2/heme oxygenase-1 signaling pathway. CircRNA-LONP2 may serve as a new therapeutic target for atherosclerosis.

剪切敏感性 circRNA-LONP2 通过靶向 NRF2/HO1 信号促进内皮炎症和动脉粥样硬化
血流动力学剪切应力是一种作用于血管内皮细胞的摩擦力,对内皮细胞的平衡至关重要。生理性层流剪切应力(LSS)可抑制内皮炎症,保护动脉免受动脉粥样硬化。在此,我们筛选了在 LSS 刺激下内皮细胞中发生显著改变的差异表达环状 RNA(circRNA),发现环状 RNA-LONP2 参与调节流动依赖性炎症反应。此外,内皮细胞circRNA-LONP2的过表达促进了体外和体内的内皮炎症和动脉粥样硬化。从机理上讲,circRNA-LONP2竞争性疏导了miR-200a-3p,随后促进了Kelch样ECH相关蛋白1、Yes相关蛋白1和zeste同源增强子2的表达,从而使核因子红细胞2相关因子2/血红素氧合酶-1信号失活,促进了氧化应激和内皮炎症,加速了动脉粥样硬化。LSS诱导的circRNA-LONP2下调至少部分抑制了内皮炎症,因为它激活了miR-200a-3p介导的核因子红细胞2相关因子2/血红素加氧酶-1信号通路。CircRNA-LONP2 可作为动脉粥样硬化的新治疗靶点。
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来源期刊
JACC: Basic to Translational Science
JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-
CiteScore
14.20
自引率
1.00%
发文量
161
审稿时长
16 weeks
期刊介绍: JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.
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