Pharmacologic suppression of experimental abdominal aortic aneurysms: A comparison of doxycycline and four chemically modified tetracyclines

Background: Matrix metalloproteinases (MMPs) likely contribute to the degra dation of medial elastin in abdominal aortic aneurysms (AAAs), and tetracyc line antibiotics exhibit MMP-inhibiting properties. The purpose of this stu dy was to compare the effects of doxycycline and several non-antibiotic che mically modified tetracyclines (CMTs) in a rat model of elastase-induced AA A. Methods: Fifty-two male Wistar rats underwent intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase. The rats then were treat ed for 7 days with subcutaneous injections of saline solution, different do ses of doxycycline, or 1 of 4 different CMTs. The aortic diameters were mea sured with microcalipers, and the fixed tissues were examined by means of l ight microscopy. Gelatin zymography was used to assess the MMP activity in the aortic tissue extracts. Results: The mean aortic diameter in the control group increased by 126% +/ - 14% on day 7 (from 1.57 +/- 0.04 mm to 3.54 +/- 0.27 mm; P < .05), and 5 of 6 animals (83%) had AAAs. Doxycycline appeared to inhibit aortic dilatat ion in a dose-dependent manner, and AAAs did not develop in any animals. Ha lf-maximal effects were observed at a dose of approximately 6 mg/kg/day, an d maximal effects were noted at greater than 30 mg/kg/day. No AAAs were obs erved in the animals that were treated with CMTs at 15 mg/kg/day. Each of t he following CMTs exhibited an efficacy that was similar to that of doxycyc line (percent inhibition of aortic dilatation vs control; all P < .05): CMT -3 (47.6%), CMT-4 (38.9%), CMT-7 (47.6%), CMT-8 (54.0%), and doxycycline (5 1.6%). Tissues from saline solution-treated controls exhibited a transmural inflammatory response and marked destruction of the medial elastic lamella e. Tetracycline derivatives limited the disruption of medial elastin withou t appearing to alter either the inflammatory response or the rat aortic wal l production of metallogelatinases. Conclusion: Tetracycline derivatives suppress the development of AAAs after elastase-induced aortic injury in the rat. The aneurysm-suppressing effect s of doxycycline appear to be dose-dependent and distinct from its antibiot ic activities, and they coincide with the structural preservation of medial elastin fibers. Further studies are needed to explore the potential of MMP -inhibiting tetracyclines as a novel pharmacologic strategy for the suppres sion of aortic aneurysms.