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Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of g...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956869/ https://www.ncbi.nlm.nih.gov/pubmed/35334247 http://dx.doi.org/10.1016/j.redox.2022.102286 |
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author | Hieu, Vu Ngoc Thuy, Le Thi Thanh Hai, Hoang Dat, Ninh Quoc Hoang, Dinh Viet Hanh, Ngo Vinh Phuong, Dong Minh Hoang, Truong Huu Sawai, Hitomi Shiro, Yoshitsugu Sato-Matsubara, Misako Oikawa, Daisuke Tokunaga, Fuminori Yoshizato, Katsutoshi Kawada, Norifumi |
author_facet | Hieu, Vu Ngoc Thuy, Le Thi Thanh Hai, Hoang Dat, Ninh Quoc Hoang, Dinh Viet Hanh, Ngo Vinh Phuong, Dong Minh Hoang, Truong Huu Sawai, Hitomi Shiro, Yoshitsugu Sato-Matsubara, Misako Oikawa, Daisuke Tokunaga, Fuminori Yoshizato, Katsutoshi Kawada, Norifumi |
author_sort | Hieu, Vu Ngoc |
collection | PubMed |
description | BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB. APPROACH & RESULTS: We characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl(4))-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by H(2)O(2) or transforming growth factor β1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix–encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl(4)-induced mouse liver fibrosis. CONCLUSIONS: These findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease. |
format | Online Article Text |
id | pubmed-8956869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-89568692022-03-27 Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion Hieu, Vu Ngoc Thuy, Le Thi Thanh Hai, Hoang Dat, Ninh Quoc Hoang, Dinh Viet Hanh, Ngo Vinh Phuong, Dong Minh Hoang, Truong Huu Sawai, Hitomi Shiro, Yoshitsugu Sato-Matsubara, Misako Oikawa, Daisuke Tokunaga, Fuminori Yoshizato, Katsutoshi Kawada, Norifumi Redox Biol Research Paper BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB. APPROACH & RESULTS: We characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl(4))-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by H(2)O(2) or transforming growth factor β1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix–encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl(4)-induced mouse liver fibrosis. CONCLUSIONS: These findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease. Elsevier 2022-03-19 /pmc/articles/PMC8956869/ /pubmed/35334247 http://dx.doi.org/10.1016/j.redox.2022.102286 Text en © 2022 The Authors. Published by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Hieu, Vu Ngoc Thuy, Le Thi Thanh Hai, Hoang Dat, Ninh Quoc Hoang, Dinh Viet Hanh, Ngo Vinh Phuong, Dong Minh Hoang, Truong Huu Sawai, Hitomi Shiro, Yoshitsugu Sato-Matsubara, Misako Oikawa, Daisuke Tokunaga, Fuminori Yoshizato, Katsutoshi Kawada, Norifumi Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion |
title | Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion |
title_full | Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion |
title_fullStr | Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion |
title_full_unstemmed | Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion |
title_short | Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion |
title_sort | capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting mmp-1 secretion |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956869/ https://www.ncbi.nlm.nih.gov/pubmed/35334247 http://dx.doi.org/10.1016/j.redox.2022.102286 |
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