Elastase inhibitor AZD9668 treatment prevented progression of experimental abdominal aortic aneurysms

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Abstract

Objective:

Abdominal aortic aneurysm (AAA) is a particular form of arterial disease characterized by the dilation of the aortic wall and the presence of an intraluminal thrombus linked to a high proteolytic activity. The aim of this study was to investigate the effect of an elastase inhibitor (AZD9668 from AstraZeneca) on aneurysm progression.

Methods:

For this purpose, we have used a rat model of elastase perfusion followed by repeated injection of Porphyromonas gingivalis (Pg), a weak periodontal pathogen recently reported to enhance AAA thrombus formation. Pg (1.107 colony-forming units) was injected through the jugular vein once a week for 4 weeks, and AZD9668, incorporated in the food, was delivered concomitantly.

Results:

Our results show a beneficial effect of AZD9668 treatment on AAA progression and composition. The increased AAA diameter induced by Pg was significantly reduced by AZD9668 treatment. Histologic analyses allowed us to observe the persistence of a neutrophil-rich luminal thrombus associated with calcifications in Pg-injected rats and the presence of a healing process in the Pg/AZD9668-treated group. The enhanced concentrations of markers of neutrophil activation, cell-free DNA, and myeloperoxidase and elastase activity in Pg-injected rats were significantly reduced both in the conditioned medium of AAA tissue samples and in plasma of rats injected with Pg and treated with AZD9668.

Conclusions:

AZD9668 treatment could therefore constitute a new therapeutic tool for treatment of AAA.

Clinical Relevance:

Elastase is a leukocyte protease that plays a critical role in the development and progression of abdominal aortic aneurysm (AAA) in humans. We and others have confirmed the role of elastase in murine experimental models of AAA. In this study, we demonstrated that treatment of rats with AZD9668 (elastase inhibitor) significantly reduces the AAA size and has a beneficial effect on neutrophil activation. In this way, the use of elastase inhibitors appears to be an innovative therapeutic approach in the treatment of human AAA.

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