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(Circulation. 2009;119:426-435.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Interferon- and the Interferon-Inducible Chemokine CXCL10 Protect Against Aneurysm Formation and Rupture

Victoria L. King, PhD^*; Alexander Y. Lin, MD^*; Fjoralba Kristo, MD; Thomas J.T. Anderson, BA; Neil Ahluwalia, MD; Gregory J. Hardy, BS; A. Phillip Owens, III, PhD; Deborah A. Howatt, BS; Dongxiao Shen, PhD; Andrew M. Tager, MD; Andrew D. Luster, MD, PhD; Alan Daugherty, PhD, DSc; Robert E. Gerszten, MD

From the Cardiovascular Research Center (V.L.K., A.P.O., D.A.H., A.D.), Graduate Center for Nutritional Sciences (V.L.K., A.D.), and Graduate Center for Toxicology (A.P.O., A.D.), University of Kentucky, Lexington, Ky; Center for Immunology & Inflammatory Diseases (A.Y.L., F.K., T.J.T.A., N.A., G.J.H., D.S., A.M.T., A.D.L., R.E.G.) and Cardiovascular Research Center (A.Y.L., F.K., T.J.T.A., N.A., G.J.H., D.S., R.E.G.), Massachusetts General Hospital, Charlestown, Mass, and Harvard Medical School, Boston, Mass.

Correspondence to Robert E. Gerszten, MD, Cardiology Division and Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital–East Campus, 149 13th St, Room 8307, Charlestown, MA 02129. E-mail rgerszten{at}partners.org

Received April 23, 2008; accepted October 27, 2008.

Background— Vascular disease can manifest as stenotic plaques or ectatic aneurysms, although the mechanisms culminating in these divergent disease manifestations remain poorly understood. T-helper type 1 cytokines, including interferon- and CXCL10, have been strongly implicated in atherosclerotic plaque development.

Methods and Results— Here, we specifically examined their role in the formation of abdominal aortic aneurysms in the angiotensin II–induced murine model. Unexpectedly, we found increased suprarenal aortic diameters, abdominal aortic aneurysm incidence, and aneurysmal death in apolipoprotein E– and interferon-–deficient (Apoe^–/–/Ifng^–/–) mice compared with Apoe^–/– controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-–inducible T-cell chemoattractant CXCL10 was highly induced by angiotensin II infusion in Apoe^–/– mice, but this induction was markedly attenuated in Apoe^–/–/Ifng^–/– mice. Apoe^–/–/Cxcl10^–/– mice had decreased luminal plaque but also increased aortic size, worse morphological grades of aneurysms, and a higher incidence of death due to aortic rupture than Apoe^–/– controls. Furthermore, abdominal aortic aneurysms in Apoe^–/–/Cxcl10^–/– mice were enriched for non–T-helper type 1–related signals, including transforming growth factor-β1. Treatment of Apoe^–/–/Cxcl10^–/– mice with anti-transforming growth factor-β neutralizing antibody diminished angiotensin II–induced aortic dilation.

Conclusions— The present study defines a novel pathway in which interferon- and its effector, CXCL10, contribute to divergent pathways in abdominal aortic aneurysm versus plaque formation, inhibiting the former pathology but promoting the latter. Thus, efforts to develop antiinflammatory strategies for atherosclerosis must carefully consider potential effects on all manifestations of vascular disease.

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