MFN2型
下调和上调
脐静脉
细胞生物学
炎症
内质网
未折叠蛋白反应
内皮功能障碍
线粒体
内皮
基因剔除小鼠
生物
肿瘤坏死因子α
化学
内分泌学
内科学
医学
免疫学
线粒体融合
生物化学
受体
体外
基因
线粒体DNA
作者
Yu Zhang,Jingjing Li,Rui Xu,Xinpei Wang,Xinyi Zhao,Yuan Fang,Yupeng Chen,Shan Ma,Xiaohui Di,Wei Wu,Gang She,Zheng-Da Pang,Yidong Wang,Zhen Xing,Wenjun Xie,Xingming Deng,Xiao‐Jun Du,Yi Zhang
出处
期刊:Redox biology
[Elsevier]
日期:2023-12-01
卷期号:68: 102944-102944
标识
DOI:10.1016/j.redox.2023.102944
摘要
Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE-/- mice with pressure overload.We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE-/- background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE-/- mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE-/- mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1β), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE-/- mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development.Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE-/- mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.
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