Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization.
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.


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.
Sandberg
Wiggo J
WJ
Research Institute for Internal Medicine, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway. wiggo.sandberg@klinmed.uio.no
Yndestad
Arne
A
Øie
Erik
E
Smith
Camilla
C
Ueland
Thor
T
Ovchinnikova
Olga
O
Robertson
Anna-Karin L
AK
Müller
Fredrik
F
Semb
Anne G
AG
Scholz
Hanne
H
Andreassen
Arne K
AK
Gullestad
Lars
L
Damås
Jan Kristian
JK
Frøland
Stig S
SS
Hansson
Göran K
GK
Halvorsen
Bente
B
Aukrust
Pål
P
D000328:Adult; D000368:Aged; D000789:Angina, Unstable / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006023:Glycoproteins / Q000097:blood* / Q000378:metabolism*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood* / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood* / Q000378:metabolism*; D012422:Rupture, Spontaneous / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
D001057:Apolipoproteins E; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D020782:Matrix Metalloproteinases