Abstract 157: Bone Marrow Deficiency of the NR4A Orphan Nuclear Receptor NOR1 Accelerates Atherosclerosis by Increasing Myeloid Progenitor Cell Proliferation
The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation during atherosclerosis formation. In the present study, we characterize NOR1 as a suppressor of hematopoietic stem cell proliferation. NOR1 deficiency in mice induces the expansion of myeloid progenitor cells in the bone marrow resulting in monocytosis and splenomegaly in mice. In addition to increasing the proliferation of macrophage dendritic cell progenitors (MDP), NOR1 depletion induces a proinflammatory phenotype with increased numbers of Ly6+ monocytes. Bone marrow transplantation experiments confirmed monocytosis and increased Ly6+ monocytes in mice reconstituted with NOR1-deficient bone marrow, indicative of a defect intrinsic to the transplanted hematopoietic cells. Using a thioglycollate-induced peritonitis model, deletion of the NOR1 locus was associated with increased recruitment of macrophages into the exudate following peritoneal lavage. Finally, we demonstrate that bone marrow transplantation of lethally irradiated apoE-deficient mice with NOR1-deficient hematopoietic stem cells increases atherosclerosis formation following Western diet feeding. Collectively, these experiments point to a previously unrecognized role of NOR1 in the suppression of myeloid progenitor cell proliferation, inflammatory responses, and atherosclerosis.
- © 2012 by American Heart Association, Inc.