Abstract 12934: Inhibition of Notch Reduces Incidence of Aortic Abdominal Aneurysm by Preventing Macrophage-Mediated Inflammation
Abdominal aortic aneurysm (AAA) is characterized by extensive and permanent remodeling of the aortic wall that results in a potentially life-threatening condition. AAA is associated with chronic transmural inflammation and increased proteolytic activity that degrades extracellular matrix in the aortic wall and depletes vascular smooth muscle cells. Apart from playing integral role in vascular development and remodeling, Notch1 signaling is increasingly regarded as a significant contributor to the inflammatory pathways. The objective of the study is to determine if inhibition of Notch1 signaling alters the progression of AAA in the angiotensin II (AngII) induced mouse model. Notch1 haploinsufficient mice on ApoE−/− background had a statistically significant reduction in the development of AAA (2/10=20%) after 28 days of AngII (1000ng/min/kg) infusion as compared to ApoE−/− mice (8/10=80%, p <0.05). As expected, ApoE−/− mice developed extensive abdominal aneurysms characterized by elastin degradation, apoptosis, increased macrophage recruitment, and increased monocyte chemotactic protein-1 (MCP-1) expression. Double immunostaining revealed strong correlation of these inflammatory markers with Notch1 activation. Examination of ApoE−/−Notch1+/- mice after 28 days of AngII infusion demonstrated reasonably well-defined lumen with no elastin degradation. In addition, there was negligible inflammatory macrophages and MCP-1 expression as determined by immunostaining after 7 and 28 days of AngII infusion. In an ex-vivo primary macrophage cell culture, Notch1 deficiency also decreased the expression of MCP-1, interleukin-6 and tumor necrosis factor-α in response to exogenous inflammatory stimulus (LPS; 100 ng/ml). Consistent with a protective role for Notch1 in the inflammatory response, pharmacological inhibition of Notch with DAPT in ApoE−/− mice reduced the incidence of AAA in response to AngII. Overall, our data suggest that inhibition of Notch signaling protects against the formation of AAA by specifically preventing the recruitment of monocyte/macrophages and downregulating the inflammatory response. The beneficial effects of Notch1 inhibition may lead to the development of novel therapeutics for the treatment of AAA.
- © 2011 by American Heart Association, Inc.