Wnt5a/Ror2 pathway contributes to the regulation of cholesterol homeostasis and inflammatory response in atherosclerosis |
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| Affiliation: | 1. Department of Laboratory Medicine, Suzhou Municipal Hospital North, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215008, China;2. Department of Laboratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China;3. Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215008, China;1. Department of Anesthesiology, Fujian Provincial Maternity and Children´s Hospital, Affiliated Hospital of Fujian Medical University, 18 Daoshan Road, Fuzhou, 350001 Fujian Province, China;2. Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, 253 Industrial Road, Guangzhou, 510282 Guangdong Province, China;3. Department of Clinical Laboratory, Fujian Provincial Maternity and Children´s Hospital, Affiliated Hospital of Fujian Medical University, 18 Daoshan Road, Fuzhou, 350001 Fujian Province, China;1. Department of Neurosurgery, Shanxi Provincial People''s Hospital, Taiyuan, China;2. Department of Neurosurgery, General Hospital of TISCO, Shanxi Medical University, Taiyuan, China;1. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;2. Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea;1. Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway;2. MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King’s College London, SE1 9RT London, UK;3. Research Institute of Internal Medicine, University Hospital Rikshospitalet, 0424 Oslo, Norway;4. K.J. Jebsen Inflammation Research Centre, University of Oslo, 0318 Oslo, Norway;5. Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark;6. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway;7. Institute of clinical medicine, University of Oslo, 0424 Oslo, Norway;8. Institute of Clinical Medicine and K.J. Jebsen TREC University of Tromsø, 9037 Tromsø, Norway;9. Research Laboratory, Nordland Hospital, 8092 Bodø, Norway;10. Department of Immunology, Oslo University Hospital Rikshospitalet, 0027 Oslo, Norway |
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| Abstract: | Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE−/−) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE−/− mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by β-cyclodextrin (β-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy. |
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