Abstract 012: Vascular Smooth Muscle ADAM17 Contributes to Angiotensin II-induced Abdominal Aortic Aneurysm Formation but Not Hypertension in Mice [Session Title: Renin Angiotensin System I]

Over activation of the renin angiotensin II (AngII) system has been implicated in abdominal aortic aneurysm (AAA). However, the precise molecular mechanism(s) by which AngII promotes AAA remain insufficiently understood, which hinders pharmacological treatment. At a past AHA conference, we reported critical roles for the metalloprotease, ADAM17, and downstream EGFR transactivation, in the development of AngII-induced AAA in mice treated with a lysyl oxidase inhibitor beta-aminopropionitrile (BAPN). Specifically, we demonstrated that in the mouse AngII-induced AAA was attenuated by either deletion of ADAM17 in VSMC or treatment with an EGFR inhibitor erlotinib. To better understand the clinical relevance of these findings, we studied the effect of an ADAM17 inhibitory antibody (A9B8), which recognizes both human and mouse ADAM17. Eight-week-old male C57BL6 mice were given AngII 1000 ng/kg/min via osmotic minipumps for 4 consecutive weeks and BAPN 150 mg/kg/day in drinking water for the initial 2 weeks. Additionally, mice were given 10 mg/kg/day A9B8 or control human IgG2 i.p. injection at day 1, 7, 14 and 21. As an index for AAA formation, abdominal aortic internal diameter was measured by ultrasound at day 0, 14, 21 and 28. Aortic external diameter was also measurement at day 28. AngII/BAPN treated mice given control IgG2 have a mortality rate of 46.2% due to aortic rupture/dissection. Mortality rate in mice given A9B8 was reduced to 23.1% (n=13). Surviving IgG2 treated mice ...
Source: Hypertension - Category: Cardiology Authors: Tags: Oral Abstract Presentations Source Type: research