Elastase inhibitor AZD9668 treatment prevented progression of experimental abdominal aortic aneurysms.

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 (1.10(7) 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.

• Authors: Sandrine Delbosc, Martin Rouer, Jean-Marc Alsac, Liliane Louedec, Monique Philippe, Olivier Meilhac, Carl Whatling, Jean-Baptiste Michel
• Journal: Journal of vascular surgery (J Vasc Surg) Vol. 63 Issue 2 Pg. 486-92.e1 (Feb 2016) ISSN: 1097-6809 [Electronic] United States
• PMID: 25175632 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium Phosphates
• Pyridones
• Serine Proteinase Inhibitors
• Sulfones
• N-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide
• calcium phosphate
• Peroxidase
• Pancreatic Elastase
• Matrix Metalloproteinase 9
• Mmp9 protein, rat

Topics

• Animals
• Aorta, Abdominal (drug effects, pathology)
• Aortic Aneurysm, Abdominal (chemically induced, drug therapy, microbiology, pathology)
• Calcium Phosphates (metabolism)
• Dilatation, Pathologic
• Disease Models, Animal
• Disease Progression
• Fibrosis
• Matrix Metalloproteinase 9 (metabolism)
• Neutrophil Activation (drug effects)
• Pancreatic Elastase
• Peroxidase (metabolism)
• Porphyromonas gingivalis
• Pyridones (blood, pharmacology)
• Rats
• Serine Proteinase Inhibitors (blood, pharmacology)
• Sulfones (blood, pharmacology)
• Tissue Culture Techniques