Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: preservation of aortic elastin associated with suppressed production of 92 kD gelatinase.
OBJECTIVE
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 AAAs 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.
Petrinec
D
D
Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Liao
S
S
Holmes
D R
DR
Reilly
J M
JM
Parks
W C
WC
Thompson
R W
RW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline / Q000627:therapeutic use*; D004549:Elastin / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D007279:Injections, Subcutaneous; D008297:Male; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride; D013552:Swine
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012965:Sodium Chloride; D004549:Elastin; D010196:Pancreatic Elastase; D018093:Gelatinases; D004318:Doxycycline