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(Circulation. 2008;117:1292-1301.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

CD137 Is Expressed in Human Atherosclerosis and Promotes Development of Plaque Inflammation in Hypercholesterolemic Mice

Peder S. Olofsson, MD, PhD; Leif Å. Söderström, MD; Dick Wågsäter, PhD; Yuri Sheikine, MD, PhD; Pauline Ocaya, PhD; François Lang, DVM, PhD; Catherine Rabu, PhD; Lieping Chen, MD, PhD; Mats Rudling, MD, PhD; Pål Aukrust, MD, PhD; Ulf Hedin, MD, PhD; Gabrielle Paulsson-Berne, PhD; Allan Sirsjö, PhD; Göran K. Hansson, MD, PhD

From the Center for Molecular Medicine (P.S.O., L.A.S., Y.S., U.H., G.P.-B., G.K.H.) and Center for Metabolism and Endocrinology (M.R.), Department of Medicine, and Department of Anesthesiology and Intensive Care Medicine (P.S.O.), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Division of Biomedicine, Department of Clinical Medicine, University of Örebro, Örebro, Sweden (D.W., P.O., A.S.); Division of Nuclear Medicine/PET and Noninvasive Cardiovascular Imaging Program, Departments of Radiology and Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (Y.S.); INSERM U601, Nantes, France (F.L., C.R.); Department of Dermatology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Md (L.C.); and Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway (P.A.).

Correspondence to Peder S. Olofsson, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. E-mail Peder.Olofsson{at}ki.se

Received February 26, 2007; accepted December 28, 2007.

Background— Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis.

Methods and Results— This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E–deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8⁺ cells, and expression of the murine major histocompatibility complex class II molecule I-A^b increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines.

Conclusions— Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

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CLINICAL PERSPECTIVE

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