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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2567.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Expression of Fractalkine (CX3CL1) and its Receptor, CX3CR1, Is Elevated in Coronary Artery Disease and Is Reduced During Statin Therapy

Jan K. Damås; Agnes Boullier; Torgun Wæhre; Camilla Smith; Wiggo J. Sandberg; Simone Green; Pål Aukrust; Oswald Quehenberger

From the Department of Medicine (J.K.D., A.B., S.G., O.Q.), University of California, San Diego, La Jolla; and the Research Institute for Internal Medicine (J.K.D., T.W., C.S., W.J.S., P.A.), the Department of Cardiology (T.W.), and the Section of Clinical Immunology and Infectious Diseases (P.A.), Rikshospitalet, University of Oslo, Norway.

Correspondence to Jan K. Damås, Research Institute for Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway. E-mail j.k.damas{at}klinmed.uio.no; or Oswald Quehenberger, University of California, San Diego, Department of Medicine, La Jolla, CA 92093. E-mail oquehenberger@ucsd.edu

Objective— Recent data derived primarily from studies in animal models suggest that fractalkine (CX3CL1) and its cognate receptor, CX3CR1, play a role in atherogenesis. We, therefore, hypothesized that enhanced CX3CL1/CX3CR1 expression may promote atherogenesis in patients with coronary artery disease (CAD).

Methods and Results— We examined the plasma levels of CX3CL1 and CX3CR1 expression in peripheral blood mononuclear cells (PBMC) in various CAD populations (30 patients with previous myocardial infarction, 40 patients with stable angina, 40 patients with unstable angina, and a total of 35 controls) and used various experimental approaches to characterize CX3CL1-mediated leukocyte responses. We found that the plasma levels of CX3CL1 are greatly increased in CAD, particularly in unstable disease. The parallel increase of CX3CR1 expression in PBMC was predominantly attributable to an expansion of the CX3CR1⁺CD3⁺CD8⁺ T cell subset and was associated with enhanced chemotactic, adhesive, and inflammatory responses to CX3CL1. Statin therapy for 6 months reduced the expression of CX3CL1 and CX3CR1, reaching statistical significance for both parameters only during aggressive (atorvastatin, 80 mg qd) but not conventional (simvastatin, 20 mg qd) therapy. Consequently, the functional responses of the PBMC to CX3CL1 including migration, adhesion, and secretion of interleukin-8 were attenuated by the treatments.

Conclusion— Our results suggest that the CX3CL1/CX3CR1 dyad may contribute to atherogenesis and plaque destabilization in human CAD.

We show increased plasma levels of CX3CL1 and enhanced expression of its cognate receptor, CX3CR1, on T cells in patients with coronary artery disease. These changes were accompanied by an increased chemotactic and adhesive response to CX3CL1. Statin therapy reduced the CX3CL1/CX3CR1 levels and normalized the functional responses to CX3CL1.

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

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