Wei Wang1, Wenli Liu1,2, Trevor Fidler1, Ying Wang1, Yang Tang1, Brittany Woods3,4, Carrie Welch1, Bishuang Cai1, Carlos Silvestre-Roig5, Ding Ai2, Yong-Guang Yang6, Andres Hidalgo5,7, Oliver Soehnlein5,8,9, Ira Tabas1, Ross L Levine3,4, Alan R Tall1, Nan Wang1. 1. From the Division of Molecular Medicine, Department of Medicine (W.W., W.L., T.F., Y.W., Y.T., C.W., B.C., I.T., A.R.T., N.W.), Columbia University Medical Center, New York, NY. 2. Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, China (W.L., D.A.). 3. Human Oncology and Pathogenesis Program (B.W., R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY. 4. Leukemia Service, Department of Medicine (B.W., R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY. 5. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (C.S.-R., A.H., O.S.). 6. Columbia Center for Translational Immunology (Y.-G.Y.), Columbia University Medical Center, New York, NY. 7. Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (A.H.). 8. Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden (O.S.). 9. German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S.).
Abstract
RATIONALE: The mechanisms driving atherothrombotic risk in individuals with JAK2 V617F ( Jak2 VF) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood. OBJECTIVE: The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemic mice with hematopoietic Jak2 VF expression. METHODS AND RESULTS: Irradiated low-density lipoprotein receptor knockout ( Ldlr-/-) mice were transplanted with bone marrow from wild-type or Jak2 VF mice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2 VF mice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2 VF lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagocytosis. Jak2 VF erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a "don't-eat-me" signal. Human JAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2 VF macrophages displayed increased expression and production of proinflammatory cytokines and chemokines, prominent inflammasome activation, increased p38 MAPK (mitogen-activated protein kinase) signaling, and reduced levels of MerTK (c-Mer tyrosine kinase), a key molecule mediating efferocytosis. Increased erythrophagocytosis also suppressed efferocytosis. CONCLUSIONS: Hematopoietic Jak2 VF expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2 VF caused cellular defects in erythrocytes and macrophages, leading to increased erythrophagocytosis but defective efferocytosis. These changes promote accumulation of iron in plaques and increased necrotic core formation which, together with exacerbated proinflammatory responses, likely contribute to plaque instability.
RATIONALE: The mechanisms driving atherothrombotic risk in individuals with JAK2 V617F ( Jak2VF) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood. OBJECTIVE: The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemicmice with hematopoietic Jak2 VF expression. METHODS AND RESULTS: Irradiated low-density lipoprotein receptor knockout ( Ldlr-/-) mice were transplanted with bone marrow from wild-type or Jak2VFmice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2VFmice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2VF lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagocytosis. Jak2VF erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a "don't-eat-me" signal. HumanJAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2VF macrophages displayed increased expression and production of proinflammatory cytokines and chemokines, prominent inflammasome activation, increased p38 MAPK (mitogen-activated protein kinase) signaling, and reduced levels of MerTK (c-Mer tyrosine kinase), a key molecule mediating efferocytosis. Increased erythrophagocytosis also suppressed efferocytosis. CONCLUSIONS:Hematopoietic Jak2 VF expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2VF caused cellular defects in erythrocytes and macrophages, leading to increased erythrophagocytosis but defective efferocytosis. These changes promote accumulation of iron in plaques and increased necrotic core formation which, together with exacerbated proinflammatory responses, likely contribute to plaque instability.
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