Indomethacin reduces rates of aortic dissection and rupture of the abdominal aorta by inhibiting monocyte/macrophage accumulation in a murine model

Shota Tomida,Norifumi Nishida,Yasushi Imai,Ryozo Nagai,Hiroki Aoki,Toru Suzuki,Kenichi Aizawa

doi:10.1038/s41598-019-46673-z

Abstract

Aortic dissection is a life-threatening condition, which is characterised by separation of the constituent layers of the aortic wall. We have recently shown that monocyte/macrophage infiltration into the aortic wall is a pathogenic mechanism of the condition. In the present study, we investigated whether the anti-inflammatory agent, indomethacin, could inhibit monocyte/macrophage accumulation in the aortic wall and ensuing dissection. Indomethacin was administered (from 3 days prior with daily oral administration) to mice in which aortic dissection was induced using beta-aminopropionitrile (BAPN) and angiotensin II (Ang II) infusion (2 weeks). Indomethacin prevented death from abdominal aortic dissection and decreased incidence of aortic dissection by as high as 40%. Histological and flow cytometry analyses showed that indomethacin administration resulted in inhibition of monocyte transendothelial migration and monocyte/macrophage accumulation in the aortic wall. These results indicate that indomethacin administration reduces rate of onset of aortic dissection in a murine model of the condition.

Highlights

Aortic dissection is characterized by separation of the layers that compose the aortic wall[1,2]
We previously demonstrated that infiltration of macrophages in the aorta coupled with local and/or systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulation is essential for onset of aortic dissection in a murine model involving direct application of calcium chloride to the aorta and continuous administration of angiotensin II (Ang II)[1]
Mice infused with BAPN/Ang II without indomethacin administration died of aortic rupture as early as on the third day and the survival rate dropped to approximately 40% in 2 weeks, whereas with indomethacin administration, none of the mice developed abdominal aortic rupture (Fig. 1a)

Summary

Introduction

Aortic dissection is characterized by separation of the layers that compose the aortic wall[1,2]. The abdominal aortic wall from mice infused with BAPN/Ang II showed an increase in the number of monocytes/macrophages (lymphocyte antigen 6 complex locus G6D (Ly6G)− CD11b+ CD45+). BAPN/ Ang II-infused mice exhibited fewer monocytes/macrophages, whereas the number of neutrophils, dendritic cells, or T cells did not significantly increase or decrease (Fig. 2a and Supplementary Fig. 1).

Results

Conclusion