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

Castigliano Bhamidipati, Gaurav S. Mehta, Guanyi Lu, Christopher W. Moehle, Carlos Barbery, Paul D. Dimusto, Adriana Laser, Irving L. Kron, Gilbert R. Upchurch, Gorav Ailawadi

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)238-246
Number of pages9
JournalSurgery (United States)
Volume152
Issue number2
DOIs
StatePublished - Aug 1 2012
Externally publishedYes

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Adventitia
Aortic Aneurysm
Doxycycline
Pancreatic Elastase
Aneurysm
Abdominal Aortic Aneurysm
Matrix Metalloproteinases
Immunohistochemistry
Elastin
Matrix Metalloproteinase 9
Sodium Chloride
Caspase 3
Smooth Muscle Myocytes
Smooth Muscle
Aorta
Dilatation
Up-Regulation
Swine
Macrophages
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Surgery

Cite this

Bhamidipati, C., Mehta, G. S., Lu, G., Moehle, C. W., Barbery, C., Dimusto, P. D., ... Ailawadi, G. (2012). Development of a novel murine model of aortic aneurysms using peri-adventitial elastase. Surgery (United States), 152(2), 238-246. https://doi.org/10.1016/j.surg.2012.02.010

Development of a novel murine model of aortic aneurysms using peri-adventitial elastase. / Bhamidipati, Castigliano; Mehta, Gaurav S.; Lu, Guanyi; Moehle, Christopher W.; Barbery, Carlos; Dimusto, Paul D.; Laser, Adriana; Kron, Irving L.; Upchurch, Gilbert R.; Ailawadi, Gorav.

In: Surgery (United States), Vol. 152, No. 2, 01.08.2012, p. 238-246.

Research output: Contribution to journalArticle

Bhamidipati, C, Mehta, GS, Lu, G, Moehle, CW, Barbery, C, Dimusto, PD, Laser, A, Kron, IL, Upchurch, GR & Ailawadi, G 2012, 'Development of a novel murine model of aortic aneurysms using peri-adventitial elastase', Surgery (United States), vol. 152, no. 2, pp. 238-246. https://doi.org/10.1016/j.surg.2012.02.010
Bhamidipati, Castigliano ; Mehta, Gaurav S. ; Lu, Guanyi ; Moehle, Christopher W. ; Barbery, Carlos ; Dimusto, Paul D. ; Laser, Adriana ; Kron, Irving L. ; Upchurch, Gilbert R. ; Ailawadi, Gorav. / Development of a novel murine model of aortic aneurysms using peri-adventitial elastase. In: Surgery (United States). 2012 ; Vol. 152, No. 2. pp. 238-246.
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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.",
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AU - Lu, Guanyi

AU - Moehle, Christopher W.

AU - Barbery, Carlos

AU - Dimusto, Paul D.

AU - Laser, Adriana

AU - Kron, Irving L.

AU - Upchurch, Gilbert R.

AU - Ailawadi, Gorav

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N2 - 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.

AB - 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.

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