Abstract 299: Inducible Depletion of TGF-ß1 Exerts Differential Regional Effects on AngII-Induced Aortic Aneurysms
Introduction and Objectives: Infusion of AngII into normolipidemic mice leads to uniform expansion of the ascending aorta and a low incidence of abdominal aortic aneurysms. Co-administration of the monoclonal antibody 1D11, which recognizes TGFβ 1, 2, and 3, leads to greatly increased incidences of aortic rupture in both the ascending and abdominal aorta. The purpose of this study was to determine the role of TGFβ1 in AngII-induced aortic diseases. To perform this study, TGFβ1 floxed mice were bred to express an inducible form of Cre under control of the ubiquitous promoter, chicken α- actin.
Methods and Results: Experimental mice were produced by breeding male Cre-ERT2 to female TGF-β1 floxed mice. At 8 weeks of age, male and female non-Cre littermates (N=16 male, 21 female) and TGF-β1 x Cre-ERT2 (N=11 male, 22 female) mice were injected with tamoxifen (25-75 mg/kg, i.p.) daily for 5 consecutive days. After 3 weeks, serum TGF-β1 was measured by ELISA. Serum concentrations of TGF-β1 decreased significantly in tamoxifen-injected Cre-ERT2 mice (P=0.001) compared to non-Cre littermates. Mice were then infused with AngII (1,000 ng/kg/min) for 28 days. AngII-induced increases in systolic blood pressures were not influenced by depletion of TGFβ1. AngII-induced expansion and rupture of the ascending aorta were not influenced by reduced TGFβ1. In contrast, there was marked enhancement of AngII-induced aortic expansion in the abdominal aorta (1.3 ± 0.3 versus 2.3 ± 0.3 mm in Cre- and Cre+ mice, respectively. P=0.019). Depletion of TGFβ1 had no effect on AngII-induced aortic pathologies in female mice.
Conclusion: Depletion of TGF-β1 exerted regional-specific effects on AngII-induced aortic pathologies, with enhancement of abdominal aneurysms and no effect on ascending aortic dilation.
Author Disclosures: D.L. Rateri: None. D.A. Howatt: None. A. Balakrishnan: None. J.J. Moorleghen: None. L.A. Cassis: None. A. Daugherty: None.
- © 2014 by American Heart Association, Inc.