Deficiency of the NR4A Orphan Nuclear Receptor NOR1 Decreases Monocyte Adhesion and Atherosclerosis

Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0200, USA.
Circulation Research (Impact Factor: 11.02). 08/2010; 107(4):501-11. DOI: 10.1161/CIRCRESAHA.110.222083
Source: PubMed


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.
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.
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.
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.

Download full-text


Available from: Alan Daugherty
  • Source
    • "In vivo, NR4A1-deficient bone marrow cells increased atherosclerosis development in LDLRÀ/À mice after bone marrow transplantation [53]. Pro-atherogenic activity of NR4A3 was notably associated with increased monocyte adhesion to endothelial cells [54] and the stimulation of smooth muscle cells proliferation [55]. However, the impact of NR4A3 in the progression of atherosclerosis may be cell-type dependent since a recent paper described that deficiency of NR4A3 in hematopoietic stem cells accelerates atherosclerosis [56]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of innovative anti-aging strategy is urgently needed to promote healthy aging and overcome the occurrence of age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. Genomic instability, deregulated nutrient sensing and mitochondrial dysfunction are established hallmark of aging. Interestingly, the orphan nuclear receptors NR4A subfamily (NR4A1, NR4A2 and NR4A3) are nutrient sensors that trigger mitochondria biogenesis and improve intrinsic mitochondrial function. In addition, NR4A receptors are components of DNA repair machinery and promote DNA repair. Members of the NR4A subfamily should also be involved in anti-aging properties of hormesis since these receptors are induced by various form of cellular stress and stimulate protective cells response such as anti-oxidative activity and DNA repair. Previous studies reported that NR4A nuclear receptors subfamily is potential therapeutic targets for the treatment of age related disorders (e.g. metabolic syndromes, diabetes and neurodegenerative diseases). Consequently, we propose that targeting NR4A receptors might constitute a new approach to delay aging and the onset of diseases affecting our aging population. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Dec 2014 · Medical Hypotheses
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A type of connectionist network, called the binary relation inference network, has been recently applied to solve constrained optimization problems, such as the shortest path problem, assignment problem, etc. The inherently parallel operating nature of the network promises a potential speedup in solving the problems. In some situations where the problems cannot be solved directly with the network, it is possible to have the network acting as an embedded real-time engine to solve the involved subproblems. In this paper, the possibility of embedding the network to solve the inverse shortest paths problem is explored. Limitations in incorporating the network are discussed and remedies are suggested
    Preview · Conference Paper · Jul 1994
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have investigated the classical attenuation decomposition and base material decomposition CT algorithms invented by Alvarez and Macovski in 1976 for their ability to provide quantitative atomic number Z of a given attenuator. For this purpose we have generated attenuation functions of the elements from Z = 1 to Z = 20 from measured attenuation data. We have fitted these functions to two sets of base functions: 1. the photoelectric absorption + Klein-Nishina scattering model and 2. the effective bone and water attenuator model. The results indicate model mismatches in the range of DeltaZ = plusmn0.5 for the base material decomposition and DeltaZ = plusmn0.7 for the attenuation decomposition
    No preview · Conference Paper · Nov 2005
Show more