A novel chronic advanced stage abdominal aortic aneurysm murine model

Abstract

Objective The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). Materials and methods 120 eight-week old C56BL/6 male mice were equally divided into three groups: 1) BAPN Group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice two days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μl of heat de-activated elastase. 2) Elastase Group: Mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μl of active form elastase (10.3mg protein/ml, 5.9units/mg protein) was applied on top of adventitia of infrarenal abdominal aorta for 5 minutes. 3) BAPN+Elastase Group: Mice were given both BAPN drinking water and active form of elastase application as above. On post-operative days 7, 14, 21, 28 and 100, aortic samples were collected for histology, cytokine array and gelatin zymography after aortic diameter measurement. Results Compared with Elastase group, BAPN+Elastase group had higher AAA formation rate (93% vs 65%, P < .01) with more advanced-staged AAAs (25/42 vs 1/40 for Stage II & III, P < .001). Aneurysms from the BAPN+Elastase Group demonstrated persistent long-term growth (221.5 ± 36.6%, 285.8 ± 78.6%, 801 ± 160% on day 21, 28 and 100 respectively, P ˂ .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-MMP9, IL-1β, IL-6, CCL-5, TREM-1, MCP-1 and TIMP-1) in BAPN+Elastase Group were higher than Elastase Group on day 7. After day 7, cytokine levels returned to baseline with the exception of elevated MMP2 activity. By histology, CD3⁺T cells in the BAPN+Elastase Group were elevated on days 28 and 100. Conclusions A combination of oral BAPN administration and peri-aortic elastase application induced a chronic, advanced staged AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should utilize this model, especially for examining tissue remodeling during the late stages of aneurysm development.

Antithrombotic therapy in abdominal aortic aneurysm: beneficial or detrimental?

“…44 Recent addition of BAPN (inhibitor of lysly oxidase) to the drinking water of the elastase aneurysm model does result in spontaneous ILT formation, similar to humans. 45 Furthermore, although human aneurysms have an abundance of neutrophil infiltration (;70% neutrophil contribution), most animal models are characterized by high monocyte/macrophage and lymphocyte infiltration (;10% neutrophil contribution). 46,47 However, although it is difficult to model a complex and heterogenous pathophysiology in animal models, these models are still useful to define mechanisms and pathways that may affect the human condition and provide complementary studies to test targeted therapeutics.…”

Propagation-based phase-contrast synchrotron imaging of aortic dissection in mice: from individual elastic lamella to 3D analysis

“…In combination with AngII, a blood pressure elevator, AD and aneurysms are induced in these mice 22 . Research has indicated that, compared to other mouse models, the BAPN + AngII mice are more prone to develop medial ruptures 25 – 27 . This observation and the fact that the BAPN + AngII infusion leads to aneurysm- and dissection-like symptoms 22 , 25 , 26 may explain the recent surge in research papers that use the BAPN mice and rats as a model for aneurysms 25 , 27 , dissections 22 , or both 23 .…”

Dipeptidyl peptidase-4 is increased in the abdominal aortic aneurysm vessel wall and is associated with aneurysm disease processes

“…In another study, DPP4 inhibition decreased the formation of aneurysm, elastin degradation, expression of MMP2 and -9, gelatinolytic activity, aortic apoptotic signal and macrophage infiltration in a mouse model, with similar results shown for GLP-1 [14]. All animal model have different limitations and studying DPP4 inhibition in other recently developed models could yield additional insight [45,46]. Further, DPP4 is known to interact with fibronectin and collagen [47,48], and has been shown to be involved in a complex with fibroblast activation protein α that locally degraded ECM thus enabling endothelial cell invasion and migration [49].…”