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Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model
Published on: August 25, 2020
Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 V617F Mice
Wei Wang1, Wenli Liu1,2, Trevor Fidler1
1From 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.
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.
Insights
Hematopoietic JAK2 V617F expression accelerates atherosclerosis by impairing erythrocyte and macrophage function. This leads to increased plaque complexity and instability, highlighting a novel mechanism for atherothrombotic risk.
Area of Science:
- Cardiovascular Biology
- Hematology
- Immunology
Background:
- Mechanisms of atherothrombotic risk in JAK2 V617F positive clonal hematopoiesis or myeloproliferative neoplasms are not well understood.
- JAK2 V617F is a common mutation in myeloproliferative neoplasms, associated with increased cardiovascular risk.
Purpose of the Study:
- To investigate the impact of hematopoietic JAK2 V617F expression on atherosclerosis development and underlying mechanisms in a mouse model.
- To assess the role of cellular defects in erythrocytes and macrophages in promoting plaque progression.
Main Methods:
- Hypercholesterolemic low-density lipoprotein receptor knockout mice received bone marrow transplants from wild-type or JAK2 V617F expressing mice.
- Mice were fed a high-fat, high-cholesterol Western diet to induce atherosclerosis.
- Hematopoietic function, atherosclerosis progression, cellular composition of lesions, and macrophage efferocytosis were characterized.
Main Results:
- JAK2 V617F expression significantly increased atherosclerosis development and lesion complexity.
- Lesions exhibited increased neutrophil infiltration, erythrophagocytosis, and iron deposition.
- JAK2 V617F erythrocytes showed reduced CD47 expression, increasing their phagocytosis.
- JAK2 V617F macrophages displayed heightened inflammation, inflammasome activation, and impaired efferocytosis due to reduced MerTK signaling.
Conclusions:
- Hematopoietic JAK2 V617F expression promotes early atherosclerosis and advanced plaque complexity.
- Cellular defects in JAK2 V617F erythrocytes and macrophages contribute to increased erythrophagocytosis and defective efferocytosis.
- These alterations promote iron accumulation and necrotic core formation, exacerbating inflammation and plaque instability, thus increasing atherothrombotic risk.
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