There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Matrix metalloproteinases (MMPs) likely contribute to the degradation of medial elastin
in abdominal aortic aneurysms (AAAs), and tetracycline antibiotics exhibit MMP-inhibiting
properties. The purpose of this study was to compare the effects of doxycycline and
several non-antibiotic chemically modified tetracyclines (CMTs) in a rat model of
elastase-induced AAA.
Fifty-two male Wistar rats underwent intraluminal perfusion of the abdominal aorta
with porcine pancreatic elastase. The rats then were treated for 7 days with subcutaneous
injections of saline solution, different doses of doxycycline, or 1 of 4 different
CMTs. The aortic diameters were measured with microcalipers, and the fixed tissues
were examined by means of light microscopy. Gelatin zymography was used to assess
the MMP activity in the aortic tissue extracts.
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 dilatation in a dose-dependent manner, and
AAAs did not develop in any animals. Half-maximal effects were observed at a dose
of approximately 6 mg/kg/day, and maximal effects were noted at greater than 30 mg/kg/day.
No AAAs were observed in the animals that were treated with CMTs at 15 mg/kg/day.
Each of the following CMTs exhibited an efficacy that was similar to that of doxycycline
(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 (51.6%). Tissues from saline
solution-treated controls exhibited a transmural inflammatory response and marked
destruction of the medial elastic lamellae. Tetracycline derivatives limited the disruption
of medial elastin without appearing to alter either the inflammatory response or the
rat aortic wall production of metallogelatinases.
Tetracycline derivatives suppress the development of AAAs after elastase-induced aortic
injury in the rat. The aneurysm-suppressing effects of doxycycline appear to be dose-dependent
and distinct from its antibiotic 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 suppression
of aortic aneurysms.