Erythroid lineage [Jak2.sup.V617F] expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis

• Published in: The Journal of clinical investigation Vol. 132; no. 13
• Main Authors: Liu, Wenli, Ostberg, 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
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01-07-2022
• Subjects: Atherosclerosis; Development and progression; Erythrocytes; Genetic aspects; Health aspects; Macrophages; Phagocytosis; Physiological aspects; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI155724

Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The [JAK2.sup.V617F] ([JAK2.sup.VF]) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. [JAK2.sup.VF] mice with elevated WBCs, platelets, and RBCs display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid [JAK2.sup.VF] expression promotes atherosclerosis, we developed hyperlipidemic erythropoietin receptor Cre mice that express [JAK2.sup.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.sup.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.sup.VF] chimeric mice simulating clonal hematopoiesis, but had no impact in controls. Erythroid lineage [JAK2.sup.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.