on November 29, 2007
Published online before print November 29, 2007, doi: 10.1161/ATVBAHA.107.147827
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 10, 2007
Accepted on November 20, 2007
CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor–Deficient Mice
Eva J.A. van Wanrooij ;
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, Gorlaeus Laboratories, The Netherlands; and UCB (H.L.B., D.A.O., R.J.W., G.A.C.), Granta Park, Great Abington, Cambridge, UK.
* To whom correspondence should be addressed. E-mail: j.kuiper{at}lacdr.leidenuniv.nl.
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.
This article has been cited by other articles:
 |
|
 |
|
  H.-H. Hsu, K. Duning, H. H. Meyer, M. Stolting, T. Weide, S. Kreusser, T. van Le, C. Gerard, R. Telgmann, S.-M. Brand-Herrmann, et al. Hypertension in mice lacking the CXCR3 chemokine receptor Am J Physiol Renal Physiol, April 1, 2009; 296(4): F780 - F789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B.K. Schwarz, N. Langwieser, N. N. Langwieser, M. J. Bek, S. Seidl, H.-H. Eckstein, B. Lu, A. Schomig, H. Pavenstadt, and D. Zohlnhofer Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury: Involvement of mTORC1 Circ. Res., January 30, 2009; 104(2): 189 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zernecke, E. Shagdarsuren, and C. Weber Chemokines in Atherosclerosis: An Update Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1897 - 1908. [Abstract] [Full Text] [PDF]
|
|