Qing Publishes Findings that NOR1 Inhibits Progenitor Proliferation

Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis. Qing H, Liu Y, Zhao Y, Aono J, Jones KL, Heywood EB, Howatt D, Binkley CM, Daugherty A,  Liang Y, Bruemmer D. Stem Cells. 2014 May 8. doi: 10.1002/stem.1747. [Epub] PMID: 24806827 

Abstract

Objective: The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In the present study, we employed bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Methods and Results: 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. Conclusion: 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 pro-atherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation. Stem Cells 2014.

Copyright © 2014 AlphaMed Press.