TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice
Open Access
- 1 February 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (2), 422-432
- https://doi.org/10.1172/jci38136
Abstract
Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II–dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II–induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.Keywords
This publication has 63 references indexed in Scilit:
- Whole genome expression analysis within the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic aneurysmBMC Genomics, 2009
- Interferon-γ and the Interferon-Inducible Chemokine CXCL10 Protect Against Aneurysm Formation and RuptureCirculation, 2009
- Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell diseaseJCI Insight, 2008
- Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic AneurysmJournal of Vascular Research, 2008
- Angiotensin II Type 1 Receptor 1166C Polymorphism Is Associated With Abdominal Aortic Aneurysm in Three Independent CohortsArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in miceJCI Insight, 2007
- Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysmsProceedings of the National Academy of Sciences of the United States of America, 2007
- Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan SyndromeScience, 2006
- Transforming growth factor-β in T-cell biologyNature Reviews Immunology, 2002
- Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.JCI Insight, 1998