Development of a novel murine model of aortic aneurysms using peri-adventitial elastase.

Abstract

BACKGROUND:

Our aim was to establish a novel model of abdominal aortic aneurysms (AAA) in mice using application of peri-adventitial elastase.

METHODS:

C57BL/6J male mice underwent infrarenal peri-adventitial application of either (1) sodium chloride (control; n = 7), (2) porcine pancreatic elastase (PPE; n = 14), or (3) PPE and doxycycline (PPE + doxycycline 200 mg/kg; n = 11) for 14 days. Aortas were analyzed by video micrometry, immunohistochemistry, qualitative polymerase chain reaction, and zymography. Groups underwent Mann-Whitney U comparisons.

RESULTS:

At day 14 compared with baseline, control animals had minimal aortic dilation, whereas fusiform aneurysms were seen in PPE (control, 20 ± 3%; PPE, 82 ± 15%; P ≤ .003). Doxycycline abrogated aneurysm formation (PPE, 82 ± 15%; PPE + doxycycline, 37 ± 10%; P ≤ .03). Compared with control and PPE + doxycycline, immunohistochemistry demonstrated greater elastin fiber degradation, macrophage infiltration, and matrix metalloproteinase-9 expression in PPE. Ki-67 and cleaved caspase-3 were lower in control versus PPE. The loss of smooth muscle marker expression seen with PPE was preserved in PPE + doxycycline. Zymography confirmed that both MMP-2 and -9 were more active in PPE than PPE + doxycycline.

CONCLUSION:

Peri-adventitial application of elastase is a simple, reproducible in vivo model of aneurysm formation leading to consistent infrarenal aortic aneurysm development by day 14, with inflammatory cell infiltration and MMP upregulation. Doxycycline inhibits AAA progression in this model via limiting matrix degradation and preserving differentiated smooth muscle cells.

• Authors: Castigliano M Bhamidipati, Gaurav S Mehta, Guanyi Lu, Christopher W Moehle, Carlos Barbery, Paul D DiMusto, Adriana Laser, Irving L Kron, Gilbert R Upchurch Jr, Gorav Ailawadi
• Journal: Surgery (Surgery) Vol. 152 Issue 2 Pg. 238-46 (Aug 2012) ISSN: 1532-7361 [Electronic] United States
• PMID: 22828146 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Mosby, Inc. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Pancreatic Elastase
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Doxycycline

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Aortic Aneurysm, Abdominal (chemically induced, drug therapy, enzymology)
• Disease Models, Animal
• Doxycycline (therapeutic use)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Pancreatic Elastase
• Swine