TY - JOUR
T1 - Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm
T2 - Preservation of aortic elastin associated with suppressed production of 92 kD gelatinase
AU - Petrinec, D.
AU - Liao, S.
AU - Holmes, D. R.
AU - Reilly, J. M.
AU - Parks, W. C.
AU - Thompson, R. W.
N1 - Funding Information:
Supported by a Faculty Fellowship from the American College of Surgeons (RWT) and Grant HL29594 (WCP) from the National Institutes of Health.
PY - 1996
Y1 - 1996
N2 - Purpose: Increased local production of matrix metalloproteinases (MMPs) is a potential mechanism underlying structural protein degradation in abdominal aortic aneurysms (AAA). With an elastase-induced rodent model of AAA, we determined whether pharmacologic treatment with an MMP-inhibiting tetracycline might limit the development of experimental AAA in vivo. Methods: Forty-eight Wistar rats underwent a 2-hour perfusion of the abdominal aorta with 50 U porcine pancreatic elastase and were then treated with either subcutaneous doxycycline (25 mg/day; n = 24) or saline solution vehicle (n = 24). Aortic diameter was measured before and after elastase perfusion was performed and before the rats were killed at 0, 2, 7, or 14 days, and AAA were defined as an increase in aortic diameter to at least twice that before perfusion. At death the aortic tissues were either perfusion-fixed for histologic evaluation or extracted for substrate zymographic evaluation. Results: Aortic diameter was not different between groups at 0 or 2 days, but it was significantly less in animals treated with doxycycline at both 7 and 14 days (mean ± SEM, p < 0.01). After day 2 the incidence of AAA was reduced from 83% (10 of 12 rats treated with saline solution) to 8% (1 of 12 animals treated with doxycycline). By histologic assessment doxycycline prevented the structural deterioration of aortic elastin without decreasing the influx of inflammatory cells. Increased aortic wall production of 92 kD gelatinase observed in a saline solution-treated control group was markedly suppressed in animals treated with doxycycline. Conclusions: Treatment with an MMP-inhibiting tetracycline inhibits the development of experimental AAA in vivo. This inhibition may be due to selective blockade of elastolytic MMP expression in infiltrating inflammatory cells. Additional experiments, however, are necessitated to fully delineate this process.
AB - Purpose: Increased local production of matrix metalloproteinases (MMPs) is a potential mechanism underlying structural protein degradation in abdominal aortic aneurysms (AAA). With an elastase-induced rodent model of AAA, we determined whether pharmacologic treatment with an MMP-inhibiting tetracycline might limit the development of experimental AAA in vivo. Methods: Forty-eight Wistar rats underwent a 2-hour perfusion of the abdominal aorta with 50 U porcine pancreatic elastase and were then treated with either subcutaneous doxycycline (25 mg/day; n = 24) or saline solution vehicle (n = 24). Aortic diameter was measured before and after elastase perfusion was performed and before the rats were killed at 0, 2, 7, or 14 days, and AAA were defined as an increase in aortic diameter to at least twice that before perfusion. At death the aortic tissues were either perfusion-fixed for histologic evaluation or extracted for substrate zymographic evaluation. Results: Aortic diameter was not different between groups at 0 or 2 days, but it was significantly less in animals treated with doxycycline at both 7 and 14 days (mean ± SEM, p < 0.01). After day 2 the incidence of AAA was reduced from 83% (10 of 12 rats treated with saline solution) to 8% (1 of 12 animals treated with doxycycline). By histologic assessment doxycycline prevented the structural deterioration of aortic elastin without decreasing the influx of inflammatory cells. Increased aortic wall production of 92 kD gelatinase observed in a saline solution-treated control group was markedly suppressed in animals treated with doxycycline. Conclusions: Treatment with an MMP-inhibiting tetracycline inhibits the development of experimental AAA in vivo. This inhibition may be due to selective blockade of elastolytic MMP expression in infiltrating inflammatory cells. Additional experiments, however, are necessitated to fully delineate this process.
UR - http://www.scopus.com/inward/record.url?scp=0030025802&partnerID=8YFLogxK
U2 - 10.1016/S0741-5214(96)70279-3
DO - 10.1016/S0741-5214(96)70279-3
M3 - Article
C2 - 8637112
AN - SCOPUS:0030025802
SN - 0741-5214
VL - 23
SP - 336
EP - 346
JO - Journal of Vascular Surgery
JF - Journal of Vascular Surgery
IS - 2
ER -