1. Deficiency of ATP-binding cassette transporter B6 in megakaryocyte progenitors accelerates atherosclerosis in mice
- Author
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Sandra Abramowicz, Andrew J. Murphy, Nan Wang, Laurent Yvan-Charvet, Nora Bijl, Marit Westerterp, Carrie L. Welch, John D. Schuetz, Vincent Sarrazy, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Translational Immunology Groningen (TRIGR)
- Subjects
Chemokine ,Time Factors ,Atherosclerosis/blood ,ATP-binding cassette transporter ,Inbred C57BL ,Mice ,Megakaryocyte ,Receptors ,Receptors, LDL/genetics ,Platelet ,Thrombopoiesis ,Chemokine CCL5 ,Cells, Cultured ,Bone Marrow Transplantation ,Genetics ,Mice, Knockout ,Cultured ,biology ,Chemistry ,Ligand (biochemistry) ,medicine.anatomical_structure ,Biochemistry ,Disease Progression ,Female ,Blood Platelets/metabolism ,Cardiology and Cardiovascular Medicine ,Megakaryocyte Progenitor Cells/metabolism ,Blood Platelets ,Cells ,Knockout ,LDL/genetics ,Chemokine CCL5/metabolism ,Reactive Oxygen Species/metabolism ,medicine ,Animals ,Platelet activation ,Mean platelet volume ,Megakaryocyte Progenitor Cells ,Cell Proliferation ,Animal ,Atherosclerosis ,Platelet Activation ,Molecular biology ,ATP-Binding Cassette Transporters/deficiency ,Transplantation ,Mice, Inbred C57BL ,Disease Models, Animal ,Receptors, LDL ,Gene Expression Regulation ,Disease Models ,biology.protein ,ATP-Binding Cassette Transporters ,Reactive Oxygen Species - Abstract
Objective— The ATP-binding cassette (ABC) transporter B6 (ABCB6) is highly expressed in megakaryocyte progenitors, but its role in platelet production and disease has not been elucidated. Approach and Results— Among various ABC transporters, ABCB6 was highly expressed in megakaryocyte progenitors, exhibiting the same pattern of expression of genes involved in heme synthesis pathway. Transplantation of Abcb6 deficient ( Abcb6 −/− ) bone marrow into low density lipoprotein receptor deficient recipient mice resulted in expansion and proliferation of megakaryocyte progenitors, attributable to increased reactive oxygen species production in response to porphyrin loading. The enhanced megakaryopoiesis in Abcb6 −/− bone marrow–transplanted mice was further illustrated by increased platelet counts, mean platelet volume, and platelet activity. Platelets from Abcb6 −/− bone marrow–transplanted mice had higher levels of chemokine (C-C motif) ligand 5, which was associated with increased plasma chemokine (C-C motif) ligand 5 levels. There were also increased platelet–leukocyte aggregates, which resulted in leukocyte activation. Abcb6 −/− bone marrow–transplanted mice had accelerated atherosclerosis which was associated with deposition of the chemotactic agent, chemokine (C-C motif) ligand 5 in atherosclerotic plaques, resulting in increased macrophage accumulation. Conclusions— Our findings identify a new role of ABCB6 in preventing atherosclerosis development by dampening platelet production, reactivity, and chemokine (C-C motif) ligand 5 deposition in atherosclerotic lesions.
- Published
- 2014