Activation of Nrf2 inhibits atherosclerosis in ApoE−/− mice through suppressing endothelial cell inflammation and lipid peroxidation
Lei He,
Qinghua Chen,
Li Wang,
Yujie Pu,
Juan Huang,
Chak Kwong Cheng,
Jiang-Yun Luo,
Lijing Kang,
Xiao Lin,
Li Xiang,
Liang Fang,
Ben He,
Yin Xia,
Kathy O. Lui,
Yong Pan,
Jie Liu,
Cheng-Lin Zhang,
Yu Huang
Affiliations
Lei He
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
Qinghua Chen
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
Li Wang
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
Yujie Pu
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
Juan Huang
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
Chak Kwong Cheng
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
Jiang-Yun Luo
School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China
Lijing Kang
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
Xiao Lin
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
Li Xiang
State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, PR China
Liang Fang
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
Ben He
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
Yin Xia
School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China
Kathy O. Lui
Department of Chemical Pathology, and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, PR China
Yong Pan
Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China
Jie Liu
Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China
Cheng-Lin Zhang
Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China; Corresponding author. Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, PR China.
Yu Huang
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; Corresponding author. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China.
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 Cdh5CreCas9floxed-stopApoE−/− 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 Cdh5CreCas9floxed-stopApoE−/− 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.
