دورية أكاديمية
Activation of Nrf2 inhibits atherosclerosis in ApoE -/- mice through suppressing endothelial cell inflammation and lipid peroxidation.
| العنوان: | Activation of Nrf2 inhibits atherosclerosis in ApoE -/- mice through suppressing endothelial cell inflammation and lipid peroxidation. |
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| المؤلفون: | He L; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China; School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China., Chen Q; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China., Wang L; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China., Pu Y; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China., Huang J; School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China; Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, PR China., Cheng CK; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China., Luo JY; School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China., Kang L; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China., Lin X; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA., Xiang L; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, PR China., Fang L; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China., He B; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China., Xia Y; School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China., Lui KO; Department of Chemical Pathology, and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, PR China., Pan Y; Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China., Liu J; Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China., Zhang CL; Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China. Electronic address: zhangchenglin07@szu.edu.cn., Huang Y; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China; School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China. Electronic address: yu.huang@cityu.edu.hk. |
| المصدر: | Redox biology [Redox Biol] 2024 Aug; Vol. 74, pp. 103229. Date of Electronic Publication: 2024 Jun 06. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| مواضيع طبية MeSH: | Apolipoproteins E*/genetics , Apolipoproteins E*/deficiency , Apolipoproteins E*/metabolism , Atherosclerosis*/metabolism , Atherosclerosis*/genetics , Atherosclerosis*/pathology , Endothelial Cells*/metabolism , Inflammation*/metabolism , Inflammation*/genetics , Lipid Peroxidation* , NF-E2-Related Factor 2*/metabolism , NF-E2-Related Factor 2*/genetics, Animals ; Humans ; Male ; Mice ; Disease Models, Animal ; Mice, Knockout ; Oxidative Stress |
| مستخلص: | Background: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. Methods: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE -/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5 Cre Cas9 floxed-stop ApoE -/- mice. Results: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE -/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5 Cre Cas9 floxed-stop ApoE -/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. Conclusions: Upon HCD feeding in ApoE -/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis. Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
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| فهرسة مساهمة: | Keywords: Atherosclerosis; Endothelial cells; Inflammation; Lipid peroxidation; Nuclear erythroid 2-related factor 2 |
| المشرفين على المادة: | 0 (Apolipoproteins E) 0 (NF-E2-Related Factor 2) 0 (Nfe2l2 protein, mouse) 0 (Apoe protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240613 Date Completed: 20240617 Latest Revision: 20240717 |
| رمز التحديث: | 20240717 |
| مُعرف محوري في PubMed: | PMC11247299 |
| DOI: | 10.1016/j.redox.2024.103229 |
| PMID: | 38870781 |
| قاعدة البيانات: | MEDLINE |
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