Abstract
Objective:
Based on its role in inflammation and matrix degradation, we hypothesized a role for osteoprotegerin (OPG), RANK, and RANK ligand (RANKL) in coronary artery disease.
Methods and results:
We examined the expression of various members of the OPG/RANKL/RANK axis in patients with stable and unstable angina and in the atherosclerotic lesions of apolipoprotein E-deficient (apoE(-/-)) mice. Our findings were: (1) Serum levels of OPG were raised in patients with unstable angina (n=40), but not in those with stable angina (n=40), comparing controls (n=20); (2) mRNA levels of RANKL were increased in T-cells in unstable angina patients accompanied by increased expression of RANK in monocytes; (3) strong immunostaining of OPG/RANKL/RANK was seen within thrombus material obtained at the site of plaque rupture during acute myocardial infarction; (4) OPG/RANKL/RANK was expressed in the atherosclerotic plaques of apoE(-/-) mice, with RANKL located specifically to the plaques; and (5) RANKL enhanced the release of monocyte chemoattractant peptide-1 in mononuclear cells from unstable angina patients, and promoted matrix metalloproteinase (MMP) activity in vascular smooth muscle cells.
Conclusions:
We show enhanced expression of the OPG/RANKL/RANK system both in clinical and experimental atherosclerosis, with enhanced T-cell expression of RANKL as an important feature of unstable disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Angina, Unstable / immunology
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Angina, Unstable / metabolism*
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Angina, Unstable / pathology
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Animals
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Atherosclerosis / immunology
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Atherosclerosis / metabolism*
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Atherosclerosis / pathology
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Carrier Proteins / metabolism*
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Cell Line
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Female
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Glycoproteins / blood*
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Glycoproteins / metabolism*
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Humans
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Male
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Matrix Metalloproteinases / metabolism
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Knockout
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Middle Aged
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Monocytes / metabolism
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / blood*
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Tumor Necrosis Factor / blood*
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Receptors, Tumor Necrosis Factor / metabolism*
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Rupture, Spontaneous / immunology
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Rupture, Spontaneous / metabolism
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T-Lymphocytes / metabolism*
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T-Lymphocytes / pathology
Substances
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Apolipoproteins E
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Carrier Proteins
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Glycoproteins
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Membrane Glycoproteins
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Matrix Metalloproteinases