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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:857.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Enhanced T-Cell Expression of RANK Ligand in Acute Coronary Syndrome

Possible Role in Plaque Destabilization

Wiggo J. Sandberg; Arne Yndestad; Erik Øie; Camilla Smith; Thor Ueland; Olga Ovchinnikova; Anna-Karin L. Robertson; Fredrik Müller; Anne G. Semb; Hanne Scholz; Arne K. Andreassen; Lars Gullestad; Jan Kristian Damås; Stig S. Frøland; Göran K. Hansson; Bente Halvorsen; Pål Aukrust

From the Research Institute for Internal Medicine (W.J.S., A.Y., C.S., T.U., H.S., J.K.D., S.S.F., B.H., P.A.), Institute for Surgical Research (E.O.), Section of Endocrinology (T.U.), Department of Cardiology (A.K.A., L.G.), Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), Institute of Microbiology (E.O., F.M.), Rikshospitalet, University of Oslo; Diakonhjemmet Hospital (A.G.S.), Oslo, Norway; Department of Medicine and Centre for Molecular Medicine (A.-K.L.R., G.K.H.), Karolinska University Hospital, Stockholm, Sweden.

Correspondence to Wiggo J. Sandberg, MSc, Research Institute for Internal Medicine, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway. E-mail wiggo.sandberg{at}klinmed.uio.no

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.

We show enhanced expression of osteoprotegerin (OPG), RANK, and RANK ligand (RANKL) in clinical and experimental atherosclerosis with enhanced T-cell expression of RANKL as an important feature of unstable disease, further supporting a role for the OPG/RANKL/RANK axis in atherogenesis and plaque destabilization.

Key Words: arteriosclerosis • inflammation • plaque stability

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