Abstract 099: EGF Receptor Inhibitor Erlotinib Prevented Abdominal Aortic Aneurysm But Not Hypertension Induced By Angiotensin II Plus Beta-aminopropionitrile

Abstract

Enhancement of the renin angiotensin II (AngII) system has been implicated in the development of abdominal aortic aneurysm (AAA). However, detailed molecular mechanism(s) by which AngII promotes AAA remain uncertain. We have demonstrated the critical role of a metalloprotease, ADAM17, in AngII-induced EGF receptor (EGFR) transactivation and subsequent hypertrophy in vascular smooth muscle cells (VSMC). In caveolin 1-/- mice, AAA formation induced by AngII plus beta-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, was attenuated. The attenuation of AAA formation was associated with suppression of ADAM17 induction and EGFR activation. Others have reported that systemic ADAM17 silencing attenuated CaCl2-induced AAA formation in mice. We hypothesized that pharmacological inhibition of EGFR may prevent AAA but not hypertension in mice co-infused with Ang II and BAPN via suppression of ER/oxidative stress. To test this hypothesis, 8 week old mice were co-treated with AngII 1000 ng/kg/min (4 weeks) and BAPN 150 mg/kg/day (2weeks) with or without erlotinib (8 mg/kg/day), and AAA formation was evaluated by echo (internal diameter) and measurement (external diameter) of the aortae. In mice with the co-infusion, 64.3% (9/14) were dead due to aortic rupture/dissection. All surviving mice with co-infusion had AAA with max external/internal diameter (mm) of 2.12±0.31/2.06±0.47 vs 1.01±0.22/1.06±0.02 with saline infusion (p<0.01). In contrast, erlotinib-treated mice with co-infusion did not die or develop AAA. The max external/internal diameter (mm) of AA in this treatment was 1.19±0.18/1.06±0.10. In contrast, both erlotinib-treated and non-treated mice with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 147±7 vs 151±12). The EGFR inhibition was also associated with lack of EGFR activation, ADAM17 induction, ER/oxidative stress and extravascular fibrosis/matrix deposition. In conclusion, vascular EGFR activation appears to contribute to AAA formation but not hypertension induced by AngII plus BAPN. The mechanism by which EGFR promotes AAA seems to involve induction of ER stress and oxidative stress.