Abstract 17161: Adenosine A2A Receptor Limits Aortic Aneurysm Progression by Inhibiting Inflammation
Background: Chronic inflammation is a key pathologic process in the progression of aortic aneurysms (AA). Adenosine A2A receptor (A2AR) activation is known to have anti-inflammatory effects in ischemia-reperfusion injury, but the effects in AA are unknown. Therefore we hypothesized that A2AR plays an important role in AA pathogenesis by limiting chronic inflammation.
Methods: Human abdominal aortic aneurysms or donor transplant (healthy) aorta were harvested and analyzed for A2AR gene expression by real-time PCR. In separate experiments, an elastase (or saline control) perfusion model of mouse abdominal AA formation was used to assess C57BL/6 (WT) or A2AR knockout (A2ARKO) mice. At day 14, aortic diameters were measured by video micrometry, and harvested to assess either histology or A2AR gene expression. Immunohistochemistry was used to quantify neutrophils, macrophages, CD3+ T-cells, and MMP-9 protein. Movat Pentachrome stain was used to identify the elastic layer of the aortic wall. Groups underwent Mann-Whitney U test comparison.
Results: A2AR gene expression was significantly higher in human AA tissue (n=7) compared to healthy aorta (n=9, P=0.016). WT mice formed larger aneurysms with elastase (n=12) versus saline (n=11) perfusion (107±4.9% increase vs. 39±6.1% increase, P<0.001). A2AR gene expression in WT mice was also higher following elastase (n=8) versus saline (n=6) perfusion (P<0.005). After elastase perfusion, A2ARKO had larger aneurysms than WT mice (190±21.7% increase vs. 107±4.9% increase, P=0.006, n=12 each). Importantly, infiltration of neutrophils (P=0.029), macrophages (P=0.029), and CD3+ T-cells (P=0.016) was greater in A2ARKO compared to WT animals. Furthermore, MMP-9 protein was increased (P=0.029), and Movat stains showed greater degradation of elastic fibers in A2ARKO mice.
Conclusions: Endogenous A2AR plays an important role in AA progression by attenuating inflammation. These results suggest that immune cell recruitment, and degradation of elastic fibers are influenced by adenosine-mediated signaling. A2AR-targeted agonism may be a novel treatment strategy for AA-related inflammation in patients with aneurysms.
- © 2010 by American Heart Association, Inc.