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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
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.
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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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