Li Zhao, Martin Marcy, Zhang Jin, Huang Hsi-Yuan, Bai Liang, Zhang Jiao, Kang Jian, He Ming, Li Jie, Maurya Mano R, Gupta Shakti, Zhou Guangjin, Sangwung Panjamaporn, Xu Yong-Jiang, Lei Ting, Huang Hsien-Da, Jain Mohit, Jain Mukesh K, Subramaniam Shankar, Shyy John Y-J
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.).
Circulation. 2017 Oct 3;136(14):1315-1330. doi: 10.1161/CIRCULATIONAHA.117.027462. Epub 2017 Aug 9.
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.
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.
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.
KLF4 transactivates Ch25h and LXR, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.
动脉粥样硬化是一种多方面的炎症性疾病，涉及血管壁中的细胞（如内皮细胞[ECs]）以及循环和驻留的免疫原性细胞（如单核细胞/巨噬细胞）。25-羟基胆固醇作为肝脏X受体（LXR）的配体，但却是固醇调节元件结合蛋白2（SREBP2）的抑制剂，其催化酶胆固醇-25-羟化酶（Ch25h）在调节ECs和单核细胞/巨噬细胞的细胞炎症状态和胆固醇生物合成中起重要作用。
利用生物信息学分析研究RNA测序数据，以鉴定受Krüppel样因子4（KLF4）调节的胆固醇氧化和流出基因。随后，采用涉及培养的ECs和巨噬细胞的体外实验以及涉及Ch25h基因敲除小鼠的体内方法，探讨KLF4-Ch25h/LXR的抗动脉粥样硬化作用。
血管保护刺激通过KLF4增加Ch25h和LXR的表达。KLF4-Ch25h/LXR稳态轴通过抑制炎症发挥作用，这在ECs中炎性小体活性降低以及巨噬细胞中M1向M2表型转变的促进中得到证明。载脂蛋白E/Ch25h基因敲除小鼠中动脉粥样硬化的增加进一步证明了KLF4-Ch25h/LXR轴在血管功能和疾病中的有益作用。
KLF4反式激活Ch25h和LXR，从而促进ECs和巨噬细胞之间的协同作用，以预防动脉粥样硬化易感性。
