JAK2V617F Promotes Atherosclerosis

Abstract

Myeloproliferative disorder (MPD) patients are at high risk of atherothrombotic events including myocardial infarction and stroke. The somatic mutation (JAK2V617F) is commonly found in MPD patients and is associated with increased vascular risk. Moreover, the prevalence of JAK2V617F mutation is also significantly increased in non-MPD coronary artery disease (CAD) and peripheral artery disease (PAD) patients compared to the general population. Our goal was to investigate potential mechanisms of accelerated atherothrombosis using a JAK2V617F mouse model.Subletahlly irradiated Ldlr-/- mice were transplanted with bone marrow cells from wild type (WT) or Mx1-Cre/Jak2V617F (Jak2VF) mice and fed a high fat high cholesterol Western type diet (WTD). After 7 weeks of WTD Jak2VFmice had sustained neutrophilia, monocytosis and erythrocytosis; despite lower plasma cholesterol levels they showed ~1.6 fold larger atherosclerotic lesions in the aortic root (p=0.003) and accelerated carotid artery thrombosis (FeCl3 injury). After 12 weeks of WTD feeding, lesion area was only increased 1.3-fold compared to controls but showed features of plaque instability (increased necrotic core area). Early lesions (7 weeks) displayed significantly increased neutrophils (p=0.05, n=7) but not Mac 3+ macrophages. The increased neutrophil infiltration in Jak2VF mice correlated with atherosclerotic lesion size (p=0.001, r=0.78), suggesting a critical role of neutrophils in early atherogenesis. Advanced lesions (12 weeks) also showed significantly increased neutrophil (p=0.001) and macrophage (p=0.05) infiltration. No difference in CD3+ T cells or CD41+ platelet infiltration was observed at either time-point. In addition, five out of nine Jak2VF mice had prominent iron deposition (Prussian blue) and RBC marker Ter-119 staining in advanced atherosclerotic lesions (p<0.05). RBC marker Ter-119 co-localized with Mac-3(+) macrophages surrounding necrotic cores, indicating erythrophagocytosis and plaque instability.In summary, the Jak2V617F mutation promotes early atherosclerotic lesion development and plaque instability in advanced lesions. Neutrophil infiltration appears to be an important contributor to both early lesion development and necrotic core formation. These studies also suggest a novel role for RBC infiltration, iron deposition and erythrophagocytosis in advanced lesional necrotic core formation in JAK2V617F mice. DisclosuresLevine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Tall:Amgen: Consultancy; CSL Behring: Consultancy.