Deficiency of the NR4A orphan nuclear receptor NOR1 decreases monocyte adhesion and atherosclerosis.
BACKGROUND
The orphan nuclear receptor NOR1 is a member of the evolutionary highly conserved and ligand-independent NR4A subfamily of the nuclear hormone receptor superfamily. Members of this subfamily have been characterized as early response genes regulating essential biological processes including inflammation and proliferation; however, the role of NOR1 in atherosclerosis remains unknown.


OBJECTIVE
The goal of the present study was to determine the causal contribution of NOR1 to atherosclerosis development and to identify the mechanism by which this nuclear receptor participates in the disease process.


RESULTS
In the present study, we demonstrate expression of NOR1 in endothelial cells of human atherosclerotic lesions. In response to inflammatory stimuli, NOR1 expression is rapidly induced in endothelial cells through a nuclear factor kappaB-dependent transactivation of the NOR1 promoter. Overexpression of NOR1 in human endothelial cells increased the expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule-1, whereas NOR1 deficiency altered adhesion molecule expression in response to inflammatory stimuli. Transient transfection experiments and chromatin immunoprecipitation assays revealed that NOR1 induces VCAM-1 promoter activity by binding to a canonical response element for NR4A receptors in the VCAM-1 promoter. Further functional studies confirmed that NOR1 mediates monocyte adhesion by inducing VCAM-1 and intercellular adhesion molecule-1 expression in endothelial cells. Finally, we demonstrate that NOR1 deficiency reduces hypercholesterolemia-induced atherosclerosis formation in apoE(-/-) mice by decreasing the macrophage content of the lesion.


CONCLUSIONS
In concert, these studies identify a novel pathway underlying monocyte adhesion and establish that NOR1 serves a previously unrecognized atherogenic role in mice by positively regulating monocyte recruitment to the vascular wall.
Zhao
Yue
Y
Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0200, USA.
Howatt
Deborah A
DA
Gizard
Florence
F
Nomiyama
Takashi
T
Findeisen
Hannes M
HM
Heywood
Elizabeth B
EB
Jones
Karrie L
KL
Conneely
Orla M
OM
Daugherty
Alan
A
Bruemmer
Dennis
D
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency* / Q000378:metabolism; D011987:Receptors, Steroid / Q000172:deficiency* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000172:deficiency* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C490412:NR4A3 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D019010:Vascular Cell Adhesion Molecule-1