Abstract 248: TGF-β Neutralization Attenuates AngII-Induced Ascending Aortic Aneurysms While Not Affecting Abdominal Aortic Aneurysms

Abstract

Introduction and Objectives: We have demonstrated previously that angiotensin II (AngII) induces ascending and abdominal aortic aneurysms (AA) in C57BL/6 mice. In an experimental mouse model of Marfan’s Syndrome that expresses Fbn1 C1039G/+ , ascending AAs were prevented by both a neutralizing antibody to transforming growth factor-β (TGF-β) signaling and the Ang II receptor antagonist, losartan. Conversely, it has been recently reported that a neutralizing TGF-β antibody leads to abdominal aortic rupture during AngII infusion. The aim of this study was to determine the effects of a TGF-β neutralizing antibody on AngII-induced ascending and abdominal AA formation in normolipidemic mice. Methods and Results: Eight week old, male, C57BL/6 mice were fed a normal laboratory diet and infused subcutaneously with AngII (1,000 ng/kg/min) by osmotic mini-pumps for 28 days. Mice were injected intraperitoneally with control IgG (R&D Systems, AB-105-C, 10 mg/kg twice a week), or TGF-β IgG antibody (R&D Systems, AB-100-NA, 10 mg/kg per week or twice a week; n=10 mice per group). There were no changes in body weight among the groups. As expected, both doses of TGF-β antibody significantly decreased serum TGF-β concentration (P<0.05). Ascending aortic area was significantly reduced in mice administered with TGF-β antibody at 10 mg/kg twice per week, compared to mice injected with control IgG (P=0.002). There was no difference of incidence of abdominal AA among the control and TGF-β IgG antibody groups. Conclusion: In agreement with the effects of TGF-β neutralization in the Fbn1 C1039G/+ transgenic mouse, ascending AA were attenuated by the TGF-β neutralizing antibody during AngII infusion. However, we were unable to replicate the recent finding that TGF-β neutralization leads to increased rupture of abdominal aortas during AngII infusion.