TY - JOUR
T1 - Interferon-γ and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture
AU - King, Victoria L.
AU - Lin, Alexander Y.
AU - Kristo, Fjoralba
AU - Anderson, Thomas J.T.
AU - Ahluwalia, Neil
AU - Hardy, Gregory J.
AU - Owens, A. Phillip
AU - Howatt, Deborah A.
AU - Shen, Dongxiao
AU - Tager, Andrew M.
AU - Luster, Andrew D.
AU - Daugherty, Alan
AU - Gerszten, Robert E.
PY - 2009/1/27
Y1 - 2009/1/27
N2 - 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-γ 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-γ-deficient (Apoe-/-/Ifng -/-) mice compared with Apoe-/- controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-γ-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 -/-/Cxc110-/- 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-/-/Cxc110 -/- mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-β1. Treatment of Apoe -/-/Cxc110-/- 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-γ 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.
AB - 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-γ 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-γ-deficient (Apoe-/-/Ifng -/-) mice compared with Apoe-/- controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-γ-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 -/-/Cxc110-/- 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-/-/Cxc110 -/- mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-β1. Treatment of Apoe -/-/Cxc110-/- 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-γ 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.
KW - Aneurysm
KW - Atherosclerosis
KW - Immunology
KW - Inflammation
KW - Mice, knockout
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U2 - 10.1161/CIRCULATIONAHA.108.785949
DO - 10.1161/CIRCULATIONAHA.108.785949
M3 - Article
C2 - 19139386
AN - SCOPUS:60549090579
SN - 0009-7322
VL - 119
SP - 426
EP - 435
JO - Circulation
JF - Circulation
IS - 3
ER -