title: Deficiency of ATP-binding cassette transporter B6 in megakaryocyte progenitors accelerates atherosclerosis in mice.
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.
  
  
  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.
authors: From Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (A.J.M.); Department of Immunology, Monash University, Melbourne, Australia (A.J.M.); Institut National de la Sante et de la Recherche Medicale U1065, Centre Mediterraneen de Medecine Molecuaire (C3M), Atip-Avenir, Nice, France (V.S., L.Y.-C.); Department of Medicine, Division of Molecular Medicine, Columbia University, New York, NY (N.W., N.B., S.A., M.W., C.B.W.); and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN (J.D.S.).
authors: Andrew J
authors: AJ
authors: Murphy
authors: Vincent
authors: V
authors: Sarrazy
authors: Nan
authors: N
authors: Wang
authors: Nora
authors: N
authors: Bijl
authors: Sandra
authors: S
authors: Abramowicz
authors: Marit
authors: M
authors: Westerterp
authors: Carrie B
authors: CB
authors: Welch
authors: John D
authors: JD
authors: Schuetz
authors: Laurent
authors: L
authors: Yvan-Charvet
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D055016:Megakaryocyte Progenitor Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D034061:Thrombopoiesis; D013997:Time Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; C514489:Abcb6 protein, mouse; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D017382:Reactive Oxygen Species; D011973:Receptors, LDL
keywords: ATP binding cassette transporter; atherosclerosis; platelet