Abstract 16311: Inhibition of TGF-Beta in the Presence of Elevated Angiotensin II is Associated With Increased Incidence of Thoracic Aortic Dissection in Apoe Deficient and Wild Type Mice
Aortic aneurysm is a life threatening condition due to the lack of symptoms and high incidence of dissection. Recent studies have shown that inhibition of TGF-beta using TGF-beta neutralising antibody (TGFB-NAB) resulted in inhibition of thoracic aortic aneurysm (TAA) and dissection (TAD) in Marfan mouse model. Inhibition of TGF-beta using losartan was able to inhibit abdominal aortic aneurysm (AAA) and dissection (AAD) in ApoE−/− infused with Angiotensin (Ang)II for 2 weeks. TGFB-NAB induced AAA and AAD in the wild type mice (C57) infused with AngII for 4 weeks. This study aimed to differentiate the effect of TGF-beta inhibition in thoracic and abdominal aorta with/without AngII infusion in the absence/presence of genetic inheritance. Male 12 week old ApoE−/− and C57 (n=10/group) were infused with either saline or subpressor dose of AngII (1000mg/kg/min) for 4 weeks in the presence/absence of TGF-beta inhibitor (TGFB-NAB; 1mg/kg/2 week or losartan; 30mg/kg/day). At the end of the experiment or at the time of aortic dissection thoracic and abdominal aorta was collected and histological sections were used to determine the presence and location of aortic dissection and/or wall structure remodelling. Saline infusion with/without TGFB-NAB or Losartan did not cause any AAD or TAD in all groups. AngII infusion in ApoE−/− resulted in 10% AAD. AngII and TGFB-NAB resulted in 10% AAD and 30% TAD while AngII and Losartan resulted in 20% TAD. In C57 AngII with/without Losartan did not cause AAD or TAD. AngII and TGFB-NAB resulted in 20% TAD. Minimal inflammatory cells were present in the arterial wall of all groups. This study indicated that the cause of AAD and TAD is diverse. AngII induced AAD in ApoE−/− and Losartan was able to inhibit AngII induced AAD while TGFB-NAB failed to prevent it. Inhibition of TGF-beta using TGFB-NAB and Losartan induced TAD in AngII infused ApoE−/−. AngII alone did not cause AAD or TAD in C57. Only when TGF-beta was inhibited with TGFB-NAB was AngII able to induced TAD. In conclusion TGF-beta inhibition using TGFB-NAB and Losartan in the presence of AngII elevation resulted in TAD but not AAD. The effect of TGF-beta inhibition was dependent on additional supporting factors including genetic background and exogenous AngII infusion.
- © 2010 by American Heart Association, Inc.