Abstract 62: Azathioprine Is Protective in Aneurysm Formation and Progression

Abstract

Objective: An aortic aneurysm is a dilatation of the arterial wall caused by destruction of its integrity, which results in often lethal vessel ruptures. Currently, only surgical treatment is available for patients with growing aortic aneurysms, therefore there is a clinical need to identify drugs to attenuate aneurysm growth. Chronic inflammation is fundamental in aneurysm pathology with excessive leukocyte infiltration. We studied the role of the immunosuppressive drug Azathioprine (AZA) in aneurysm formation. Methods and Results: To investigate AZA in aneurysm formation, we used the Angiotensin-II (AngII) aneurysm mouse model. AngII in ApoE -/- mice on a Western Type diet resulted in 11/14 (79%) mice with aneurysms, whereas only 3/13 (23%) of the AZA-treated mice developed aneurysms. In the aorta altered signalling downstream of the AngII receptor type 1 was observed on AZA treatment; phosphorylation of Jak2 and JNK was decreased and of p38 and p44/42 was increased. In addition, reduced levels of matrix metalloproteinases (MMP)2 and MMP9 and decreased leukocyte influx was observed in AZA-treated mice. To study aneurysm progression, AZA treatment was started 10 days after AngII infusion; all mice developed aneurysms, however the aneurysm type was more severe in the control group demonstrating the inhibitory effect of AZA on aneurysm progression. To delineate the mechanism of AZA protection, we performed experiments with macrophages and endothelial cells in the presence of 6-mercaptopurine (6MP), the active metabolite of AZA. Macrophages produce less IL-12 and IFNgamma and more IL-10 after 6MP incubation and endothelial cells express less CCL5 (Rantes), IL-12 and VCAM1. Adhesion of monocytes to activated endothelial cells is reduced in the presence of 6MP. These data underscore the anti-inflammatory effect of AZA on macrophages and endothelial cells, which may explain the inhibition of aneurysm formation. Conclusion: We report a protective effect of AZA in aortic aneurysm initiation and, most importantly, inhibition of progression of the disease. AZA modulates the inflammatory response of macrophages and endothelial cells, inhibits monocyte adhesion to endothelial cells, and modulates AngII signalling in the aortic vessel wall.