Elsevier

Journal of Vascular Surgery

Volume 28, Issue 6, December 1998, Pages 1082-1093
Journal of Vascular Surgery

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

Part of this work was presented in abstract form at a New York Academy of Sciences Conference on “The abdominal aortic aneurysm: genetics, pathophysiology, and molecular biology,” Mar 7–9, 1996, New York, NY.
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Abstract

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. (J Vasc Surg 1998;28:1082-93.)

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From the Department of Surgery (Drs Curci, Petrinec, Liao, and Thompson) and the Department of Cell Biology and Physiology (Dr Thompson), Washington University School of Medicine, and the Department of Oral Biology and Pathology (Dr Golub), School of Dental Medicine, State University of New York at Stony Brook.

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Supported by a faculty fellowship from the American College of Surgeons, a Research Grant-in-Aid from the American Heart Association, Missouri Affiliate, and PHS Grant R29 HL56701.

Reprint requests: Robert W. Thompson, MD, Section of Vascular Surgery, Washington University School of Medicine, 9901 Wohl Hospital, 4960 Children's Place, St Louis, MO 63110.

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