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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:614.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Enhanced Expression of the Homeostatic Chemokines CCL19 and CCL21 in Clinical and Experimental Atherosclerosis

Possible Pathogenic Role in Plaque Destabilization

Jan K. Damås; Camilla Smith; Erik Øie; Børre Fevang; Bente Halvorsen; Torgun Wæhre; Agnes Boullier; Unni Breland; Arne Yndestad; Olga Ovchinnikova; Anna-Karin L. Robertson; Wiggo J. Sandberg; John Kjekshus; Kjetil Taskén; Stig S. Frøland; Lars Gullestad; Göran K. Hansson; Oswald Quehenberger; Pål Aukrust

From the Research Institute for Internal Medicine (J.K.D., C.S., B.F., B.H., T.W., U.B., A.Y., W.J.S., S.S.F., P.A.), the Department of Cardiology (E.Ø., J.K., L.G.), the Institute for Surgical Research (E.Ø.), the Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), the Rikshospitalet-Radiumhospitalet Medical Center, and The Biotechnology Centre of Oslo (K.T.), University of Oslo, Norway; the Department of Medicine and Centre for Molecular Medicine (O.O., A.-K.L.R., G.K.H.), Karolinska University Hospital, Stockholm, Sweden; and the Department of Medicine (J.K.D., A.B., O.Q.), University of California, San Diego, La Jolla, Calif.

Correspondence to Jan Kristian Damås, Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway. E-mail j.k.damas{at}medisin.uio.no

Objective— Based on their role in T-cell homing into nonlymphoid tissue, we examined the role of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in coronary artery disease (CAD).

Methods and Results— We performed studies in patients with stable (n=40) and unstable (n=40) angina and healthy controls (n=20), in vitro studies in T-cells and macrophages, and studies in apolipoprotein-E–deficient (ApoE^–/–) mice and human atherosclerotic carotid plaques. We found increased levels of CCL19 and CCL21 within the atherosclerotic lesions of the ApoE^–/– mice, in human atherosclerotic carotid plaques, and in plasma of CAD patients. Whereas strong CCR7 expression was seen in T-cells from murine and human atherosclerotic plaques, circulating T-cells from angina patients showed decreased CCR7 expression. CCL19 and CCL21 promoted an inflammatory phenotype in T-cells and macrophages and increased matrix metalloproteinase (MMP) and tissue factor levels in the latter cell type. Although aggressive statin therapy increased CCR7 and decreased CCL19/CCL21 levels in peripheral blood from CAD patients, conventional therapy did not.

Conclusions— The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

We show increased plasma levels of the homeostatic chemokines in CCL19 and CCL21 in clinical and experimental atherosclerosis. By promoting inflammatory responses in T-cells and by inducing a matrix degrading, prothrombotic, and inflammatory phenotype in macrophages, we suggest that these chemokines could contribute to atherogenesis and plaque destabilization.

Key Words: atherosclerosis • coronary artery disease • immune system • cytokines • leukocytes

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