Erythroid lineage Jak2V617F expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis

• Published in: The Journal of clinical investigation Vol. 132; no. 13; pp. 1 - 17
• Main Authors: Liu, Wenli, Östberg, Nataliya K, Yalcinkaya, Mustafa, Dou, Huijuan, Endo-Umeda, Kaori, Tang, Yang, Hou, Xintong, Xiao, Tong, Filder, Trevor, Abramowicz, Sandra, Yang, Yong-Guang, Soehnlein, Oliver, Tall, Alan R, Wang, Nan
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2022
• Subjects: Antioxidants; Apoptosis; Arteriosclerosis; Atherosclerosis; Biomedical research; Blood platelets; Cardiovascular disease; Cardiovascular diseases; Cholesterol; Erythropoietin; Ferroptosis; Hematocrit; Lipid peroxidation; Lipids; Macrophages; Medicin och hälsovetenskap; Mutation; Myeloproliferative diseases; Phagocytosis; Polycythemia; Therapeutic targets; Vascular biology; Vascular Biology; Atherosclerosis
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/jci155724

Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2V617F (Jak2VF) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis (CH). Jak2VF mice with elevated white blood cells, platelets and red blood cells (RBCs) display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid Jak2VF expression promotes atherosclerosis, we developed hyperlipidemic Erythropoietin Receptor Cre mice that express Jak2VF 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 JAK2VF 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 Jak2VF chimeric mice simulating CH, but had no impact in controls. Erythroid lineage Jak2VF expression leads to qualitative and quantitative defects in RBCs that exacerbate atherosclerosis. Phagocytosis of RBCs by plaque macrophages promotes ferroptosis, suggesting a new therapeutic target to reduce RBC-mediated cardiovascular risk.