Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function
Fibronectin (FN) occurs as both a soluble form, in plasma and at sites of tissue injury, and a cellular form in tissue extracellular matrices (ECM). FN is critical to wound repair, ECM structure and assembly, cell adhesion and proliferation. FN is reported to play a critical role in the development,...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171830675X |
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| author | Tina Nybo Huan Cai Christine Y. Chuang Luke F. Gamon Adelina Rogowska-Wrzesinska Michael J. Davies |
| author_facet | Tina Nybo Huan Cai Christine Y. Chuang Luke F. Gamon Adelina Rogowska-Wrzesinska Michael J. Davies |
| author_sort | Tina Nybo |
| collection | DOAJ |
| description | Fibronectin (FN) occurs as both a soluble form, in plasma and at sites of tissue injury, and a cellular form in tissue extracellular matrices (ECM). FN is critical to wound repair, ECM structure and assembly, cell adhesion and proliferation. FN is reported to play a critical role in the development, progression and stability of cardiovascular atherosclerotic lesions, with high FN levels associated with a thick fibrotic cap, stable disease and a low risk of rupture. Evidence has been presented for FN modification by inflammatory oxidants, and particularly myeloperoxidase (MPO)-derived species including hypochlorous acid (HOCl). The targets and consequences of FN modification are poorly understood. Here we show, using a newly-developed MS protocol, that HOCl and an enzymatic MPO system, generate site-specific dose-dependent Tyr chlorination and dichlorination (up to 16 of 100 residues modified), and oxidation of Trp (7 of 39 residues), Met (3 of 26) and His (1 of 55) within selected FN domains, and particularly the heparin- and cell-binding regions. These alterations increase FN binding to heparin-containing columns. Studies using primary human coronary artery smooth muscle cells (HCASMC) show that exposure to HOCl-modified FN, results in decreased adherence, increased proliferation and altered expression of genes involved in ECM synthesis and remodelling. These findings indicate that the presence of modified fibronectin may play a major role in the formation, development and stabilisation of fibrous caps in atherosclerotic lesions and may play a key role in the switching of quiescent contractile smooth muscle cells to a migratory, synthetic and proliferative phenotype. Keywords: Fibronectin, Myeloperoxidase, Hypochlorous acid, 3-chlorotyrosine, Oxidation, Chlorination, Extracellular matrix, Vascular smooth muscle cells |
| first_indexed | 2024-12-10T09:10:15Z |
| format | Article |
| id | doaj.art-f3e58f24ec764afebddc146b6ef01c28 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T09:10:15Z |
| publishDate | 2018-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-f3e58f24ec764afebddc146b6ef01c282022-12-22T01:55:03ZengElsevierRedox Biology2213-23172018-10-0119388400Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell functionTina Nybo0Huan Cai1Christine Y. Chuang2Luke F. Gamon3Adelina Rogowska-Wrzesinska4Michael J. Davies5Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, DenmarkDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, DenmarkDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, DenmarkDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, DenmarkDepartment of Biochemistry and Molecular Biology and VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, DenmarkDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark; Corresponding author.Fibronectin (FN) occurs as both a soluble form, in plasma and at sites of tissue injury, and a cellular form in tissue extracellular matrices (ECM). FN is critical to wound repair, ECM structure and assembly, cell adhesion and proliferation. FN is reported to play a critical role in the development, progression and stability of cardiovascular atherosclerotic lesions, with high FN levels associated with a thick fibrotic cap, stable disease and a low risk of rupture. Evidence has been presented for FN modification by inflammatory oxidants, and particularly myeloperoxidase (MPO)-derived species including hypochlorous acid (HOCl). The targets and consequences of FN modification are poorly understood. Here we show, using a newly-developed MS protocol, that HOCl and an enzymatic MPO system, generate site-specific dose-dependent Tyr chlorination and dichlorination (up to 16 of 100 residues modified), and oxidation of Trp (7 of 39 residues), Met (3 of 26) and His (1 of 55) within selected FN domains, and particularly the heparin- and cell-binding regions. These alterations increase FN binding to heparin-containing columns. Studies using primary human coronary artery smooth muscle cells (HCASMC) show that exposure to HOCl-modified FN, results in decreased adherence, increased proliferation and altered expression of genes involved in ECM synthesis and remodelling. These findings indicate that the presence of modified fibronectin may play a major role in the formation, development and stabilisation of fibrous caps in atherosclerotic lesions and may play a key role in the switching of quiescent contractile smooth muscle cells to a migratory, synthetic and proliferative phenotype. Keywords: Fibronectin, Myeloperoxidase, Hypochlorous acid, 3-chlorotyrosine, Oxidation, Chlorination, Extracellular matrix, Vascular smooth muscle cellshttp://www.sciencedirect.com/science/article/pii/S221323171830675X |
| spellingShingle | Tina Nybo Huan Cai Christine Y. Chuang Luke F. Gamon Adelina Rogowska-Wrzesinska Michael J. Davies Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function Redox Biology |
| title | Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function |
| title_full | Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function |
| title_fullStr | Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function |
| title_full_unstemmed | Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function |
| title_short | Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function |
| title_sort | chlorination and oxidation of human plasma fibronectin by myeloperoxidase derived oxidants and its consequences for smooth muscle cell function |
| url | http://www.sciencedirect.com/science/article/pii/S221323171830675X |
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