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.

中文翻译：

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红系 Jak2V617F 表达通过红细胞吞噬作用和巨噬细胞铁死亡促进动脉粥样硬化

血细胞比容升高与心血管风险相关；然而，因果关系和机制尚不清楚。JAK2 ^V617F ( Jak2 ^VF ) 突变增加了骨髓增生性疾病和克隆性造血中的心血管风险。白细胞、血小板和红细胞升高的Jak2 ^{VF小鼠表现出加速的动脉粥样硬化和巨噬细胞红细胞吞噬作用。}为了研究选择性红细胞Jak2 ^VF表达是否促进动脉粥样硬化，我们开发了表达Jak2 ^{VF的高脂血症促红细胞生成素受体 Cre 小鼠}在红细胞谱系中（VFEpoR 小鼠）。血细胞计数未升高的 VFEpoR 小鼠显示动脉粥样硬化斑块坏死、红细胞吞噬作用和铁死亡增加。用低剂量促红细胞生成素选择性诱导红细胞增多进一步加剧了动脉粥样硬化，并伴有显着的铁死亡、脂质过氧化和内皮损伤。VFEpoR 红细胞的抗氧化防御能力降低，脂质氢过氧化物增加。WT 巨噬细胞对人或小鼠 WT 或 JAK2 ^VF红细胞的吞噬作用诱导铁死亡，铁死亡抑制剂 liproxstatin-1 可阻止这种情况。Liproxstatin-1 可逆转 VFEpoR 小鼠和Jak2 ^{VF中增加的动脉粥样硬化、脂质过氧化、铁死亡和内皮损伤}嵌合小鼠模拟克隆造血，但对对照组没有影响。红细胞谱系Jak2 ^VF表达导致红细胞的定性和定量缺陷，加剧了动脉粥样硬化。斑块巨噬细胞对红细胞的吞噬作用促进了铁死亡，表明降低红细胞介导的心血管风险的治疗靶点。