TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice

• Published in: The Journal of clinical investigation Vol. 120; no. 2; pp. 422 - 432
• Main Authors: Wang, Yu, Ait-Oufella, Hafid, Herbin, Olivier, Bonnin, Philippe, Ramkhelawon, Bhama, Taleb, Soraya, Huang, Jin, Offenstadt, Georges, Combadière, Christophe, Rénia, Laurent, Johnson, Jason L., Tharaux, Pierre-Louis, Tedgui, Alain, Mallat, Ziad
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2010
• Subjects: Angiotensin; Angiotensin II - metabolism; Angiotensin II - toxicity; Animals; Anti-Inflammatory Agents - therapeutic use; Aortic Aneurysm, Abdominal - diagnostic imaging; Aortic Aneurysm, Abdominal - drug therapy; Aortic Aneurysm, Abdominal - pathology; Aortic Aneurysm, Abdominal - prevention & control; Aortic aneurysms; Complications and side effects; Development and progression; Disease Progression; Dosage and administration; Health aspects; Immune response; Inflammation - immunology; Inflammation - physiopathology; Inflammation - prevention & control; Male; Matrix Metalloproteinase 12 - deficiency; Matrix Metalloproteinase 2 - deficiency; Mice; Mice, Inbred C57BL; Patient outcomes; Physiological aspects; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - pharmacology; Transforming growth factors; Ultrasonography; France
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI38136

Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-beta activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-beta in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-beta 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-gamma, IL-4, IL-6, or TNF-alpha signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-beta activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-beta neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-beta 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.