Neutrophil proteinase 3 — An LDL- and HDL-proteolyzing enzyme with a potential to contribute to cholesterol accumulation in human atherosclerotic lesions |
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| Institution: | 1. Wihuri Research Institute, Haartmaninkatu 8, 00290 Helsinki, Finland;2. EV Group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Finland;3. CURED, Drug Research Program, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Finland;4. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;5. Institute of Biomedicine, Department of Biochemistry and Developmental Biology, Meilahti Clinical Proteomics Core Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland;6. Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, Finland;7. Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland;8. National Institute for Health and Welfare, Helsinki, Finland;9. Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland;1. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China;2. Sanya Institute of Nanjing Agricultural University, Sanya, Hainan 572024, China;3. College of Animal Science, Fujian Agriculture & Forestry University, Fuzhou, Fujian 350002, China;1. Univ. Grenoble Alpes, Inserm, LBFA, U1055, UFR STAPS, Grenoble, France;2. LBEPS, Univ Evry, IRBA, Université Paris Saclay, Evry, France;3. Aix Marseille Univ, CNRS, CRMBM, Marseille, France;4. Univ. Grenoble Alpes, Inserm, HP2, U1042, Grenoble, France;5. Univ. Grenoble Alpes, Inserm, LBFA, U1055, CHU Grenoble Alpes, Grenoble, France;6. Univ. Grenoble Alpes, Inserm, LBFA, U1055, Grenoble, France;1. Group on the Molecular and Cell Biology of Lipids and Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada;2. Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China;1. Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montreal, QC, Canada;2. Equipe SP@RTE, UMR 6290 CNRS, Université de Rennes 1, Rennes, France;3. Nantes Université, CHU Nantes, CNRS, INSERM, l''Institut du thorax, F-44000 Nantes, France;4. Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;5. S.L. present address: Centre de recherche de l''hôpital Maisonneuve Rosemont, Montreal, QC, Canada;1. Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia;2. Autoimmune Unit, Allergy and Immunology Research Centre, Institute for Medical Research (IMR), National Institute of Health (NIH) Malaysia, No. 1, Jalan Setia Murni U13/52, Bandar Setia Alam, 40170 Shah Alam, Selangor, Malaysia;3. Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia;4. Innovation Centre for Confectionery Technology (MANIS), Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia;5. Colin Ratledge Center for Microbial Lipids, School of Agriculture Engineering and Food Sciences, Shandong University of Technology, 266 Xincun Rd., Zibo, Shandong, PR China;6. Department of Biological Sciences, University of Hull, Kingston upon Hull HU6 7RX, United Kingdom;1. Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan;2. Department of Pathology, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;3. Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan;4. Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan;5. Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan;6. Department of Anatomy and Neurobiology, Kagawa University School of Medicine, Kagawa, Japan;7. Department of Pathology and Host Defense, Kagawa University School of Medicine, Kagawa, Japan;8. Department of Molecular Neurobiology, Kagawa University School of Medicine, Kagawa, Japan;9. Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan |
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| Abstract: | Neutrophil proteinase 3 (PR3) is a multifunctional neutral serine protease involved in the regulation of pro-inflammatory processes, but its potential causal roles in the lipid-driven responses in atherosclerosis have remained unexplored. This study aimed to investigate the presence of PR3 in human atherosclerotic lesions and the ability of this protease to modify the structure and functions of LDL and HDL particles in vitro. Coronary artery segments were collected from autopsied subjects and immunostained for PR3. Atherosclerotic lesions but not normal intima contained PR3. Incubation of LDL particles with the PR3 led to extensive degradation of their apoB-100 component and strongly increased their binding strength to isolated human aortic proteoglycans in vitro. Moreover, cultured human monocyte-derived macrophages avidly ingested the PR3-modified LDL particles and were converted into foam cells. Incubation of HDL particles with PR3 led to proteolysis of their major apolipoproteins (apoA-I, apoA-II, and apoE) and impaired their ability to promote cholesterol efflux from the macrophage foam cells. We conclude that PR3 is present in human atherosclerotic lesions and that this neutral serine protease has proatherogenic properties. Thus, by proteolytically modifying LDL and HDL particles, PR3 may promote cholesterol accumulation both extra- and intracellularly in atherosclerotic lesions, and so contribute to the lipid-driven component of atherogenesis. |
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