Guanyi Lu1, Gang Su1, John P Davis1, Basil Schaheen1, Emily Downs1, R Jack Roy2, Gorav Ailawadi1, Gilbert R Upchurch3. 1. Department of Surgery, University of Virginia, Charlottesville, Va. 2. Molecular Imaging Core, Department of Radiology, University of Virginia, Charlottesville, Va. 3. Department of Surgery, University of Virginia, Charlottesville, Va. Electronic address: gru6n@virginia.edu.
Abstract
OBJECTIVE: The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). METHODS: Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative 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 the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 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-matrix metalloproteinase 9, interleukin-1β, interleukin-6, chemokine [C-C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100. CONCLUSIONS: A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.
OBJECTIVE: The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). METHODS: Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative 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 the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 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-matrix metalloproteinase 9, interleukin-1β, interleukin-6, chemokine [C-C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100. CONCLUSIONS: A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.
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Authors: William F Johnston; Morgan Salmon; Nicolas H Pope; Akshaya Meher; Gang Su; Matthew L Stone; Guanyi Lu; Gary K Owens; Gilbert R Upchurch; Gorav Ailawadi Journal: Circulation Date: 2014-09-09 Impact factor: 29.690
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Authors: Alexander H Shannon; Craig T Elder; Guanyi Lu; Gang Su; Alexis Mast; Morgan D Salmon; William G Montgomery; Michael D Spinosa; Gilbert R Upchurch; Ashish K Sharma Journal: FASEB J Date: 2020-06-07 Impact factor: 5.191
Authors: William G Montgomery; Michael D Spinosa; J Michael Cullen; Morgan D Salmon; Gang Su; Taryn Hassinger; Ashish K Sharma; Guanyi Lu; Anna Fashandi; Gorav Ailawadi; Gilbert R Upchurch Journal: Surgery Date: 2018-08-31 Impact factor: 3.982
Authors: Alexander H Shannon; Mahendra D Chordia; Michael D Spinosa; Gang Su; Zachary Ladd; Dongfeng Pan; Gilbert R Upchurch; Ashish K Sharma Journal: J Surg Res Date: 2020-03-12 Impact factor: 2.192
Authors: Anna Z Fashandi; Robert B Hawkins; Morgan D Salmon; Michael D Spinosa; William G Montgomery; J Michael Cullen; Guanyi Lu; Gang Su; Gorav Ailawadi; Gilbert R Upchurch Journal: Surgery Date: 2017-11-28 Impact factor: 3.982
Authors: J Michael Cullen; Guanyi Lu; Alexander H Shannon; Gang Su; Ashish Sharma; Morgan Salmon; Anna Z Fashandi; Michael D Spinosa; William G Montgomery; W Forrest Johnston; Gorav Ailawadi; Gilbert R Upchurch Journal: J Vasc Surg Date: 2018-12-24 Impact factor: 4.268
Authors: Gurneet S Sangha; Albert Busch; Andrea Acuna; Alycia G Berman; Evan H Phillips; Matthias Trenner; Hans-Henning Eckstein; Lars Maegdefessel; Craig J Goergen Journal: J Vasc Res Date: 2019-07-04 Impact factor: 1.934