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Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis
Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2(V617F) (Jak2(VF)) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. Jak2(VF) mice with elevated WBCs, platelets, and RBCs display...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246386/ https://www.ncbi.nlm.nih.gov/pubmed/35587375 http://dx.doi.org/10.1172/JCI155724 |
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author | Liu, Wenli Östberg, Nataliya Yalcinkaya, Mustafa Dou, Huijuan Endo-Umeda, Kaori Tang, Yang Hou, Xintong Xiao, Tong Fidler, Trevor P. Abramowicz, Sandra Yang, Yong-Guang Soehnlein, Oliver Tall, Alan R. Wang, Nan |
author_facet | Liu, Wenli Östberg, Nataliya Yalcinkaya, Mustafa Dou, Huijuan Endo-Umeda, Kaori Tang, Yang Hou, Xintong Xiao, Tong Fidler, Trevor P. Abramowicz, Sandra Yang, Yong-Guang Soehnlein, Oliver Tall, Alan R. Wang, Nan |
author_sort | Liu, Wenli |
collection | PubMed |
description | Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2(V617F) (Jak2(VF)) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. Jak2(VF) mice with elevated WBCs, platelets, and RBCs display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid Jak2(VF) expression promotes atherosclerosis, we developed hyperlipidemic erythropoietin receptor Cre mice that express Jak2(VF) in the erythroid lineage (VFEpoR mice). VFEpoR mice without elevated blood cell counts showed increased atherosclerotic plaque necrosis, erythrophagocytosis, and ferroptosis. Selective induction of erythrocytosis with low-dose erythropoietin further exacerbated atherosclerosis with prominent ferroptosis, lipid peroxidation, and endothelial damage. VFEpoR RBCs had reduced antioxidant defenses and increased lipid hydroperoxides. Phagocytosis of human or murine WT or JAK2(VF) RBCs by WT macrophages induced ferroptosis, which was prevented by the ferroptosis inhibitor liproxstatin-1. Liproxstatin-1 reversed increased atherosclerosis, lipid peroxidation, ferroptosis, and endothelial damage in VFEpoR mice and in Jak2(VF) chimeric mice simulating clonal hematopoiesis, but had no impact in controls. Erythroid lineage Jak2(VF) expression led to qualitative and quantitative defects in RBCs that exacerbated atherosclerosis. Phagocytosis of RBCs by plaque macrophages promoted ferroptosis, suggesting a therapeutic target for reducing RBC-mediated cardiovascular risk. |
format | Online Article Text |
id | pubmed-9246386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-92463862022-07-02 Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis Liu, Wenli Östberg, Nataliya Yalcinkaya, Mustafa Dou, Huijuan Endo-Umeda, Kaori Tang, Yang Hou, Xintong Xiao, Tong Fidler, Trevor P. Abramowicz, Sandra Yang, Yong-Guang Soehnlein, Oliver Tall, Alan R. Wang, Nan J Clin Invest Research Article Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2(V617F) (Jak2(VF)) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. Jak2(VF) mice with elevated WBCs, platelets, and RBCs display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid Jak2(VF) expression promotes atherosclerosis, we developed hyperlipidemic erythropoietin receptor Cre mice that express Jak2(VF) in the erythroid lineage (VFEpoR mice). VFEpoR mice without elevated blood cell counts showed increased atherosclerotic plaque necrosis, erythrophagocytosis, and ferroptosis. Selective induction of erythrocytosis with low-dose erythropoietin further exacerbated atherosclerosis with prominent ferroptosis, lipid peroxidation, and endothelial damage. VFEpoR RBCs had reduced antioxidant defenses and increased lipid hydroperoxides. Phagocytosis of human or murine WT or JAK2(VF) RBCs by WT macrophages induced ferroptosis, which was prevented by the ferroptosis inhibitor liproxstatin-1. Liproxstatin-1 reversed increased atherosclerosis, lipid peroxidation, ferroptosis, and endothelial damage in VFEpoR mice and in Jak2(VF) chimeric mice simulating clonal hematopoiesis, but had no impact in controls. Erythroid lineage Jak2(VF) expression led to qualitative and quantitative defects in RBCs that exacerbated atherosclerosis. Phagocytosis of RBCs by plaque macrophages promoted ferroptosis, suggesting a therapeutic target for reducing RBC-mediated cardiovascular risk. American Society for Clinical Investigation 2022-07-01 2022-07-01 /pmc/articles/PMC9246386/ /pubmed/35587375 http://dx.doi.org/10.1172/JCI155724 Text en © 2022 Liu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Liu, Wenli Östberg, Nataliya Yalcinkaya, Mustafa Dou, Huijuan Endo-Umeda, Kaori Tang, Yang Hou, Xintong Xiao, Tong Fidler, Trevor P. Abramowicz, Sandra Yang, Yong-Guang Soehnlein, Oliver Tall, Alan R. Wang, Nan Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
title | Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
title_full | Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
title_fullStr | Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
title_full_unstemmed | Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
title_short | Erythroid lineage Jak2(V617F) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
title_sort | erythroid lineage jak2(v617f) expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246386/ https://www.ncbi.nlm.nih.gov/pubmed/35587375 http://dx.doi.org/10.1172/JCI155724 |
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