title: 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.
  
  
  CONCLUSIONS
  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: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors: Castigliano M
authors: CM
authors: Bhamidipati
authors: Gaurav S
authors: GS
authors: Mehta
authors: Guanyi
authors: G
authors: Lu
authors: Christopher W
authors: CW
authors: Moehle
authors: Carlos
authors: C
authors: Barbery
authors: Paul D
authors: PD
authors: DiMusto
authors: Adriana
authors: A
authors: Laser
authors: Irving L
authors: IL
authors: Kron
authors: Gilbert R
authors: GR
authors: Upchurch
authors: Gorav
authors: G
authors: Ailawadi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase; D013552:Swine
chemical_list: D000900:Anti-Bacterial Agents; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D004318:Doxycycline