@article{0a7d947a15974fbe813fb0f530a0ac2f,
title = "SOX4 is a novel phenotypic regulator of endothelial cells in atherosclerosis revealed by single-cell analysis",
abstract = "Introduction: Atherosclerotic complications represent the leading cause of cardiovascular mortality globally. Dysfunction of endothelial cells (ECs) often initiates the pathological events in atherosclerosis. Objectives: In this study, we sought to investigate the transcriptional profile of atherosclerotic aortae, identify novel regulator in dysfunctional ECs and hence provide mechanistic insights into atherosclerotic progression. Methods: We applied single-cell RNA sequencing (scRNA-seq) on aortic cells from Western diet-fed apolipoprotein E-deficient (ApoE−/−) mice to explore the transcriptional landscape and heterogeneity of dysfunctional ECs. In vivo validation of SOX4 upregulation in ECs were performed in atherosclerotic tissues, including mouse aortic tissues, human coronary arteries, and human renal arteries. Single-cell analysis on human aortic aneurysmal tissue was also performed. Downstream vascular abnormalities induced by EC-specific SOX4 overexpression, and upstream modulators of SOX4 were revealed by biochemical assays, immunostaining, and wire myography. Effects of shear stress on endothelial SOX4 expression was investigated by in vitro hemodynamic study. Results: Among the compendium of aortic cells, mesenchymal markers in ECs were significantly enriched. Two EC subsets were subsequently distinguished, as the {\textquoteleft}endothelial-like{\textquoteright} and {\textquoteleft}mesenchymal-like{\textquoteright} subsets. Conventional assays consistently identified SOX4 as a novel atherosclerotic marker in mouse and different human arteries, additional to a cancer marker. EC-specific SOX4 overexpression promoted atherogenesis and endothelial-to-mesenchymal transition (EndoMT). Importantly, hyperlipidemia-associated cytokines and oscillatory blood flow upregulated, whereas the anti-diabetic drug metformin pharmacologically suppressed SOX4 level in ECs. Conclusion: Our study unravels SOX4 as a novel phenotypic regulator during endothelial dysfunction, which exacerbates atherogenesis. Our study also pinpoints hyperlipidemia-associated cytokines and oscillatory blood flow as endogenous SOX4 inducers, providing more therapeutic insights against atherosclerotic diseases.",
keywords = "Atherosclerosis, EndoMT, Endothelial cells, Shear stress, Single-cell RNA sequencing",
author = "Cheng, {Chak Kwong} and Xiao Lin and Yujie Pu and Tse, {Joyce Ka Yu} and Yu Wang and Zhang, {Cheng Lin} and Xiaoyun Cao and Lau, {Chi Wai} and Juan Huang and Lei He and Luo, {Jiang Yun} and Shih, {Yu Tsung} and Song Wan and Ng, {Chi Fai} and Li Wang and Ma, {Ronald Ching Wan} and Chiu, {Jeng Jiann} and Chan, {Ting Fung} and {Yu Tian}, Xiao and Yu Huang",
note = "Funding Information: This present study was supported by grants from National Natural Science Foundation of China ( 91939302 , 81922078 ), Hong Kong RGC -Collaborative Research Fund ( C4024-16W ), Hong Kong RGC-Senior Research Fellow Scheme ( SRFS2021-4S04 ), Hong Kong RGC-General Research Fund (14109519, 14105321), and Hong Kong RGC-Research Impact Fund ( R4012-18 ). This study was also supported by Taiwan Ministry of Science and Technology grants ( MOST 109-2326-B-400-006 and MOST 109-2320-B-400-010-MY3 ), an Innovation and Technology Fund from the Innovation and Technology Commission, Hong Kong Government to the State Key Laboratory, and a generous donation from Mr. and Mrs. Sunny Yang. The authors thank the members of core laboratory facilities (CUHK) for assistance. Funding Information: This present study was supported by grants from National Natural Science Foundation of China (91939302, 81922078), Hong Kong RGC-Collaborative Research Fund (C4024-16W), Hong Kong RGC-Senior Research Fellow Scheme (SRFS2021-4S04), Hong Kong RGC-General Research Fund (14109519, 14105321), and Hong Kong RGC-Research Impact Fund (R4012-18). This study was also supported by Taiwan Ministry of Science and Technology grants (MOST 109-2326-B-400-006 and MOST 109-2320-B-400-010-MY3), an Innovation and Technology Fund from the Innovation and Technology Commission, Hong Kong Government to the State Key Laboratory, and a generous donation from Mr. and Mrs. Sunny Yang. The authors thank the members of core laboratory facilities (CUHK) for assistance. Publisher Copyright: {\textcopyright} 2022",
year = "2023",
month = jan,
doi = "10.1016/j.jare.2022.02.017",
language = "English",
volume = "43",
pages = "187--203",
journal = "Journal of Advanced Research",
issn = "2090-1232",
publisher = "Elsevier B.V.",
}