Zhao Li1, Marcy Martin1, Jin Zhang1, Hsi-Yuan Huang1, Liang Bai1, Jiao Zhang1, Jian Kang1, Ming He1, Jie Li1, Mano R Maurya1, Shakti Gupta1, Guangjin Zhou1, Panjamaporn Sangwung1, Yong-Jiang Xu1, Ting Lei1, Hsien-Da Huang1, Mohit Jain1, Mukesh K Jain1, Shankar Subramaniam1, John Y-J Shyy2. 1. From Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (Z.L., Jin Zhang, L.B., Jiao Zhang, M.H., J.L., T.L., J.Y.-J.S.); Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China (Z.L., Jin Zhang, L.B., Jiao Zhang, M.H., J.L., T.L., J.Y.-J.S.); Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (M.M., Jin Zhang, J.K., M.H., Y.-J.X., M.J., J.Y.-J.S.);Department of Bioengineering, University of California, San Diego, La Jolla (M.R.M., S.G.); Division of Biochemistry and Molecular Biology, University of California, Riverside (M.M.); Institute of Bioinformatics and Systems Biology and Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan (H.-Y.H., H.-D.H.); and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (G.Z., P.S., M.K.J.). 2. From Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (Z.L., Jin Zhang, L.B., Jiao Zhang, M.H., J.L., T.L., J.Y.-J.S.); Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China (Z.L., Jin Zhang, L.B., Jiao Zhang, M.H., J.L., T.L., J.Y.-J.S.); Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (M.M., Jin Zhang, J.K., M.H., Y.-J.X., M.J., J.Y.-J.S.);Department of Bioengineering, University of California, San Diego, La Jolla (M.R.M., S.G.); Division of Biochemistry and Molecular Biology, University of California, Riverside (M.M.); Institute of Bioinformatics and Systems Biology and Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan (H.-Y.H., H.-D.H.); and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (G.Z., P.S., M.K.J.). jshyy@ucsd.edu.
Abstract
BACKGROUND: Atherosclerosis is a multifaceted inflammatory disease involving cells in the vascular wall (eg, endothelial cells [ECs]), as well as circulating and resident immunogenic cells (eg, monocytes/macrophages). Acting as a ligand for liver X receptor (LXR), but an inhibitor of SREBP2 (sterol regulatory element-binding protein 2), 25-hydroxycholesterol, and its catalyzing enzyme cholesterol-25-hydroxylase (Ch25h) are important in regulating cellular inflammatory status and cholesterol biosynthesis in both ECs and monocytes/macrophages. METHODS: Bioinformatic analyses were used to investigate RNA-sequencing data to identify cholesterol oxidation and efflux genes regulated by Krüppel-like factor 4 (KLF4). In vitro experiments involving cultured ECs and macrophages and in vivo methods involving mice with Ch25h ablation were then used to explore the atheroprotective role of KLF4-Ch25h/LXR. RESULTS: Vasoprotective stimuli increased the expression of Ch25h and LXR via KLF4. The KLF4-Ch25h/LXR homeostatic axis functions through suppressing inflammation, evidenced by the reduction of inflammasome activity in ECs and the promotion of M1 to M2 phenotypic transition in macrophages. The increased atherosclerosis in apolipoprotein E-/-/Ch25h-/- mice further demonstrates the beneficial role of the KLF4-Ch25h/LXR axis in vascular function and disease. CONCLUSIONS: KLF4 transactivates Ch25h and LXR, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.
BACKGROUND:Atherosclerosis is a multifaceted inflammatory disease involving cells in the vascular wall (eg, endothelial cells [ECs]), as well as circulating and resident immunogenic cells (eg, monocytes/macrophages). Acting as a ligand for liver X receptor (LXR), but an inhibitor of SREBP2 (sterol regulatory element-binding protein 2), 25-hydroxycholesterol, and its catalyzing enzyme cholesterol-25-hydroxylase (Ch25h) are important in regulating cellular inflammatory status and cholesterol biosynthesis in both ECs and monocytes/macrophages. METHODS: Bioinformatic analyses were used to investigate RNA-sequencing data to identify cholesterol oxidation and efflux genes regulated by Krüppel-like factor 4 (KLF4). In vitro experiments involving cultured ECs and macrophages and in vivo methods involving mice with Ch25h ablation were then used to explore the atheroprotective role of KLF4-Ch25h/LXR. RESULTS: Vasoprotective stimuli increased the expression of Ch25h and LXR via KLF4. The KLF4-Ch25h/LXR homeostatic axis functions through suppressing inflammation, evidenced by the reduction of inflammasome activity in ECs and the promotion of M1 to M2 phenotypic transition in macrophages. The increased atherosclerosis in apolipoprotein E-/-/Ch25h-/- mice further demonstrates the beneficial role of the KLF4-Ch25h/LXR axis in vascular function and disease. CONCLUSIONS:KLF4 transactivates Ch25h and LXR, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.
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