TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice.
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.
Wang
Yu
Y
INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes and Assistance Publique-Hôpitaux de Paris, Paris, France.
Ait-Oufella
Hafid
H
Herbin
Olivier
O
Bonnin
Philippe
P
Ramkhelawon
Bhama
B
Taleb
Soraya
S
Huang
Jin
J
Offenstadt
Georges
G
Combadière
Christophe
C
Rénia
Laurent
L
Johnson
Jason L
JL
Tharaux
Pierre-Louis
PL
Tedgui
Alain
A
Mallat
Ziad
Z
D000804:Angiotensin II / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D018450:Disease Progression; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D014463:Ultrasonography
D000893:Anti-Inflammatory Agents; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D020778:Matrix Metalloproteinase 2; D053508:Matrix Metalloproteinase 12