TY - JOUR
T1 - Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis
AU - Hamers, Anouk A.J.
AU - Vos, Mariska
AU - Rassam, Fadi
AU - Marincovic, Goran
AU - Kurakula, Kondababu
AU - Van Gorp, Patrick J.
AU - De Winther, Menno P.J.
AU - Gijbels, Marion J.J.
AU - De Waard, Vivian
AU - De Vries, Carlie J.M.
PY - 2012/2/3
Y1 - 2012/2/3
N2 - Rationale: Nuclear receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis. Methods and Results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77 -/-) mice. Nur77 -/- BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 -/- BMM cells. SDF-1α expression in nonstimulated Nur77 -/- BMM is repressed by Nur77 -/- and the chemoattractive activity of Nur77 -/- BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 -/- mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 -/- on atherosclerosis was studied in low density lipoprotein receptor-deficient (Ldlr) mice. Ldlr mice with a Nur77-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77-transplanted mice, which may explain the observed aggravation of lesion formation. Conclusions: In conclusion, in bone marrow-derived cells the nuclear receptor Nur77 -/- has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
AB - Rationale: Nuclear receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis. Methods and Results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77 -/-) mice. Nur77 -/- BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 -/- BMM cells. SDF-1α expression in nonstimulated Nur77 -/- BMM is repressed by Nur77 -/- and the chemoattractive activity of Nur77 -/- BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 -/- mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 -/- on atherosclerosis was studied in low density lipoprotein receptor-deficient (Ldlr) mice. Ldlr mice with a Nur77-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77-transplanted mice, which may explain the observed aggravation of lesion formation. Conclusions: In conclusion, in bone marrow-derived cells the nuclear receptor Nur77 -/- has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
KW - NR4A1
KW - Nur77
KW - atherosclerosis
KW - bone marrow transplantation
KW - polarization
UR - http://www.scopus.com/inward/record.url?scp=84856752344&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/CIRCRESAHA.111.260760
DO - https://doi.org/10.1161/CIRCRESAHA.111.260760
M3 - Article
C2 - 22194623
SN - 0009-7330
VL - 110
SP - 428
EP - 438
JO - Circulation Research
JF - Circulation Research
IS - 3
ER -