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. 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

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes

“…We have recently linked reticulated thrombocytosis to accelerated atherosclerosis in various genetically deficient (i.e., Abcg4 -/-and Abcb6 -/-) preclinical models (10,48). The mechanism appears to relate to increased platelet-leukocyte aggregates, leukocyte activation, and plasma levels of the potent leukocyte chemokine CCL5.…”

“…BM cells were obtained from femurs and tibias and stained with a cocktail of antibodies before analysis by flow cytometry as previously described (10,48,70 ). Cell cycle was quantified using DAPI (Sigma-Aldrich).…”

Vascular Regeneration by Stem/Progenitor Cells

“…Recently, a group of scientists discovered that the ATP-binding cassette transporter B6 was highly expressed in megakaryocyte progenitors. 67 Deletion of the ATP-binding cassette transporter B6 resulted in expansion of megakaryocyte progenitors and increased platelet counts and platelet activity.…”

“…67 Taken together, hematopoietic stem cells exert their effectiveness on atherogenesis via differentiation into macrophages/platelets or influencing lipid metabolisms.…”

The ABC of Thrombopoiesis

“…In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Murphy et al 5 show that the lack of ABCB6 in the bone marrow leads to thrombocytosis, enhanced proinflammatory platelet activity, and accelerated atherosclerosis in atherosclerosis-prone hyperlipidemic low-density lipoprotein receptor-deficient mice (see the Figure). Interestingly, ABCB6 was found to be highly expressed in bone marrow megakaryocyte progenitors.…”