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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:251.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor–Deficient Mice

Eva J.A. van Wanrooij; Saskia C.A. de Jager; Thomas van Es; Paula de Vos; Helen L. Birch; David A. Owen; Robbert J. Watson; Erik A.L. Biessen; Gayle A. Chapman; Theo J.C. van Berkel; Johan Kuiper

From the Division of Biopharmaceutics (E.J.A.v.W., S.C.A.d.J., T.v.E., P.d.V., E.A.L.B., T.J.C.v.B., J.K.), Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands; and UCB (H.L.B., D.A.O., R.J.W., G.A.C.), Granta Park, Great Abington, Cambridge, UK.

Correspondence to Johan Kuiper, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail j.kuiper{at}lacdr.leidenuniv.nl

Abstract

Objective— The chemokine receptor CXCR3 is implicated in migration of leukocytes to sites of inflammation. Antagonizing CXCR3 may be a strategy to inhibit inflammation-induced leukocyte migration and subsequently reduce atherosclerosis. We used the CXCR3 specific antagonist NBI-74330 to block CXCR3-mediated signaling in peritonitis and diet-induced atherosclerosis.

Methods and Results— Antagonizing CXCR3 with NBI-74330 resulted in a significant reduction in CD4⁺ T cell and macrophage migration to the peritoneal cavity, which was as shown in ex vivo migration studies totally CXCR3 dependent. Atherosclerotic lesion formation in the aortic valve leaflet area and the entire aorta was significantly inhibited in NBI-74330 treated mice. Lymph nodes draining from the aortic arch were significantly smaller in treated mice and were enriched in regulatory T cells and contained fewer activated T cells, whereas the markers for regulatory T cells within the lesion were enhanced after NBI-74330 treatment.

Conclusion— This study shows for the first time that treatment with a CXCR3 antagonist results in attenuating atherosclerotic lesion formation by blocking direct migration of CXCR3⁺ effector cells from the circulation into the atherosclerotic plaque and by beneficially modulating the inflammatory response in the lesion and the lymph nodes draining from the atherosclerotic lesion.

Antagonizing CXCR3 using NBI-74330 reduced atherogenesis not only by blocking direct migration of effector cells from the circulation to the atherosclerotic plaque, but also by beneficially modulating the inflammatory response in lymph nodes draining from the atherosclerotic lesion.

Key Words: atherosclerosis • CXCR3 • regulatory T cells • TGF-β • CXCL1O