Nogo-B mediates endothelial oxidative stress and inflammation to promote coronary atherosclerosis in pressure-overloaded mouse hearts.

Autor:	Zhang Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Li JJ; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China., Xu R; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China., Wang XP; Department of Aerospace Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China., Zhao XY; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Fang Y; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China., Chen YP; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Ma S; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Di XH; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China., Wu W; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., She G; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Pang ZD; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Wang YD; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China., Zhang X; Department of Aerospace Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China., Xie W; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China., Deng XL; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Du XJ; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China., Zhang Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, And Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. Electronic address: zhangyixjtu@xjtu.edu.cn.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2023 Dec; Vol. 68, pp. 102944. Date of Electronic Publication: 2023 Oct 21.
DOI:	10.1016/j.redox.2023.102944
Abstrakt:	Aims: 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. Methods and Results: 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 Ca 2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development. Conclusion: 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. Competing Interests: Declaration of competing interest The authors declare that there are no confilct of interests. (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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