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Pharmacologic suppression of experimental abdominal aortic aneurysms: acomparison of doxycycline and four chemically
J A Curci1, D Petrinec, S Liao
1Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
Background:
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.
Methods:
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.
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 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.
Conclusion:
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.
Insights
Tetracycline derivatives, including doxycycline and chemically modified tetracyclines (CMTs), effectively suppressed the development of abdominal aortic aneurysms (AAAs) in a rat model by preserving medial elastin.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are implicated in the medial elastin degradation observed in abdominal aortic aneurysms (AAAs).
- Tetracycline antibiotics possess MMP-inhibiting properties, suggesting potential therapeutic applications for AAAs.
Purpose of the Study:
- To compare the efficacy of doxycycline and novel chemically modified tetracyclines (CMTs) in preventing elastase-induced AAA formation in rats.
- To investigate the dose-dependent effects of doxycycline on AAA development.
Main Methods:
- Induction of AAA in male Wistar rats via intraluminal elastase perfusion.
- Treatment with saline, varying doses of doxycycline, or four distinct CMTs via subcutaneous injections for seven days.
- Assessment of aortic diameter changes, histological examination of aortic tissues, and MMP activity analysis using gelatin zymography.
Main Results:
- Elastase perfusion significantly increased aortic diameter and induced AAA in 83% of control rats.
- Doxycycline demonstrated dose-dependent inhibition of aortic dilatation, with maximal effect at >30 mg/kg/day.
- CMTs (CMT-3, CMT-4, CMT-7, CMT-8) at 15 mg/kg/day showed efficacy comparable to doxycycline, inhibiting AAA development and preserving medial elastin.
Conclusions:
- Tetracycline derivatives effectively suppress AAA development in a rat model, independent of their antibiotic properties.
- The aneurysm-suppressing effects are linked to the preservation of medial elastin fibers.
- MMP-inhibiting tetracyclines represent a promising novel pharmacologic strategy for AAA suppression.
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