title: Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis.
abstract: The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In this study, we used bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Reconstitution of lethally irradiated apoE(-/-) mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C(+) monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C(+) monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local proatherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation.
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, and Saha Cardiovascular Research Center, Chongqing, People's Republic of China; Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Qing
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Aono
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Deborah
authors.initials: D
authors.lastname: Howatt
authors.forename: Cassi M
authors.initials: CM
authors.lastname: Binkley
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011987:Receptors, Steroid / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone
keywords: Atherosclerosis; Macrophage and dendritic progenitors; Monocyte; Nuclear receptor