Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Inflammation is a common denominator in chronic diseases of agin...
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Public Library of Science (PLoS)
2018
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| Online Access: | http://hdl.handle.net/1721.1/116426 https://orcid.org/0000-0003-4064-2510 |
| _version_ | 1826207561078013952 |
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| author | Hayashi, Hideki Cherpokova, Deya Martinod, Kimberly Witsch, Thilo Wong, Siu Ling Gallant, Maureen Cifuni, Stephen M. Wagner, Denisa D. Guarente, Leonard Pershing |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hayashi, Hideki Cherpokova, Deya Martinod, Kimberly Witsch, Thilo Wong, Siu Ling Gallant, Maureen Cifuni, Stephen M. Wagner, Denisa D. Guarente, Leonard Pershing |
| author_sort | Hayashi, Hideki |
| collection | MIT |
| description | This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Inflammation is a common denominator in chronic diseases of aging. Yet, how inflammation fuels these diseases remains unknown. Neutrophils are the primary leukocytes involved in the early phase of innate immunity and inflammation. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs have been shown to induce tissue injury and thrombosis. Here, we demonstrated that Sirt3, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, an enzyme linked to human longevity, was expressed in mouse neutrophils and platelets. Using Sirt3-/- mice as a model of accelerated aging, we investigated the effects of Sirt3 deficiency on NETosis and platelet function, aiming to detect enhancement of thrombosis. More mitochondrial reactive oxygen species (ROS) were generated in neutrophils and platelets of Sirt3-/- mice compared to WT, when stimulated with a low concentration of phorbol 12-myristate 13-acetate (PMA) and a high concentration of thrombin, respectively. There were no differences in in vitro NETosis, with or without stimulation. Platelet aggregation was mildly augmented in Sirt3-/- mice compared to WT mice, when stimulated with a low concentration of collagen. The effect of Sirt3 deficiency on platelet and neutrophil activation in vivo was examined by the venous thrombosis model of inferior vena cava stenosis. Elevation of plasma DNA concentration was observed after stenosis in both genotypes, but no difference was shown between the two genotypes. The systemic response to thrombosis was enhanced in Sirt3-/- mice with significantly elevated neutrophil count and reduced platelet count. However, no differences were observed in incidence of thrombus formation, thrombus weight and thrombin-antithrombin complex generation between WT and Sirt3-/- mice. We conclude that Sirt3 does not considerably impact NET formation, platelet function, or venous thrombosis in healthy young mice. |
| first_indexed | 2024-09-23T13:51:28Z |
| format | Article |
| id | mit-1721.1/116426 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:51:28Z |
| publishDate | 2018 |
| publisher | Public Library of Science (PLoS) |
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| spelling | mit-1721.1/1164262022-09-28T16:40:08Z Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice Hayashi, Hideki Cherpokova, Deya Martinod, Kimberly Witsch, Thilo Wong, Siu Ling Gallant, Maureen Cifuni, Stephen M. Wagner, Denisa D. Guarente, Leonard Pershing Massachusetts Institute of Technology. Department of Biology Guarente, Leonard Pershing This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Inflammation is a common denominator in chronic diseases of aging. Yet, how inflammation fuels these diseases remains unknown. Neutrophils are the primary leukocytes involved in the early phase of innate immunity and inflammation. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs have been shown to induce tissue injury and thrombosis. Here, we demonstrated that Sirt3, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, an enzyme linked to human longevity, was expressed in mouse neutrophils and platelets. Using Sirt3-/- mice as a model of accelerated aging, we investigated the effects of Sirt3 deficiency on NETosis and platelet function, aiming to detect enhancement of thrombosis. More mitochondrial reactive oxygen species (ROS) were generated in neutrophils and platelets of Sirt3-/- mice compared to WT, when stimulated with a low concentration of phorbol 12-myristate 13-acetate (PMA) and a high concentration of thrombin, respectively. There were no differences in in vitro NETosis, with or without stimulation. Platelet aggregation was mildly augmented in Sirt3-/- mice compared to WT mice, when stimulated with a low concentration of collagen. The effect of Sirt3 deficiency on platelet and neutrophil activation in vivo was examined by the venous thrombosis model of inferior vena cava stenosis. Elevation of plasma DNA concentration was observed after stenosis in both genotypes, but no difference was shown between the two genotypes. The systemic response to thrombosis was enhanced in Sirt3-/- mice with significantly elevated neutrophil count and reduced platelet count. However, no differences were observed in incidence of thrombus formation, thrombus weight and thrombin-antithrombin complex generation between WT and Sirt3-/- mice. We conclude that Sirt3 does not considerably impact NET formation, platelet function, or venous thrombosis in healthy young mice. 2018-06-19T18:34:30Z 2018-06-19T18:34:30Z 2017-12 2017-06 2018-06-19T12:52:05Z Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/116426 Hayashi, Hideki et al. “Sirt3 Deficiency Does Not Affect Venous Thrombosis or NETosis Despite Mild Elevation of Intracellular ROS in Platelets and Neutrophils in Mice.” Edited by Nades Palaniyar. PLOS ONE 12, 12 (December 2017): e0188341 © 2017 Hayashi et al https://orcid.org/0000-0003-4064-2510 http://dx.doi.org/10.1371/JOURNAL.PONE.0188341 PLOS ONE Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | Hayashi, Hideki Cherpokova, Deya Martinod, Kimberly Witsch, Thilo Wong, Siu Ling Gallant, Maureen Cifuni, Stephen M. Wagner, Denisa D. Guarente, Leonard Pershing Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice |
| title | Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice |
| title_full | Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice |
| title_fullStr | Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice |
| title_full_unstemmed | Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice |
| title_short | Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice |
| title_sort | sirt3 deficiency does not affect venous thrombosis or netosis despite mild elevation of intracellular ros in platelets and neutrophils in mice |
| url | http://hdl.handle.net/1721.1/116426 https://orcid.org/0000-0003-4064-2510 |
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