Abstract 56: Endothelial Adam17 Contributes to Angiotensin Ii-induced Abdominal Aortic Aneurysm in Mice
Enhancement of the renin angiotensin II (AngII) system has been implicated in the development of abdominal aortic aneurysm (AAA) in animal models as well as in clinical studies. However, detailed molecular mechanism(s) by which AngII promotes AAA remain uncertain. We have demonstrated the critical roles of a metalloprotease, ADAM17, in AngII signal transduction in cultured vascular cells. Endothelial AT1 receptor has been recently implicated in oxidative stress. Interestingly, others have reported that ADAM17 expression was enhanced in CaCl2-induced AAA in mice and that systemic ADAM17 silencing attenuated AAA formation. However, the cell type that is mediating the deleterious effect of ADMA17 signaling is not well understood. Here we tested our hypothesis that endothelial ADAM17 activation is required for AngII-promoted AAA formation using ADAM17flox/flox mice bred with Tie2 Cre transgenic mice. 8 week old mice were co-infused with AngII 1000 ng/kg/min (4 weeks) and beta-aminopropionitrile, a lysyl oxidase inhibitor, 150 mg/kg/day (2weeks) or control saline (4 weeks) via osmotic mini-pump, and AAA formation was evaluated by the diameters. AAA formation was attenuated in ADAM17flox/flox Tie2 Cre(+/-) mice compared with ADAM17flox/flox Tie2 Cre(-/-) mice (1.50±0.44 mm vs 3.96±0.61 mm). Cardiac hypertrophy evaluated by heart weight body weight ratio was also attenuated in the Tie2 Cre(+/-) mice (0.0063±0.0005 vs 0.0092±0.0013). However, AngII induced hypertension to a similar degree in both mice groups, as assessed by telemetries. The ADAM17 deletion was associated with less oxidative stress as assessed by anti-nitrotyrosine IHC and less extravascular fibrosis/matrix deposition. Also, the aorta was less stained with MMP2 antibody and phospho-JNK antibody. In conclusion, endothelial ADAM17 appears to be a critical metalloprotease contributing to AAA formation and cardiac remodeling but not hypertension induced by AngII. The mechanism by which endothelial ADAM17 promotes AAA seems to involve induction of oxidative stress, JNK activation and subsequent MMP2 induction.
- © 2012 by American Heart Association, Inc.