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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:483.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Differential Effects of Doxycycline, a Broad-Spectrum Matrix Metalloproteinase Inhibitor, on Angiotensin II–Induced Atherosclerosis and Abdominal Aortic Aneurysms

Michael W. Manning; Lisa A. Cassis; Alan Daugherty

From the Department of Physiology (M.W.M., A.D.); the Division of Pharmaceutical Science, College of Pharmacy (L.A.C.); and the Division of Cardiovascular Medicine, Gill Heart Institute (A.D.), University of Kentucky, Lexington.

Correspondence to Alan Daugherty, PhD, Division of Cardiovascular Medicine, Sanders Brown, Room 424, Gill Heart Institute, University of Kentucky, Lexington, KY 40536-0230. E-mail adaugh{at}uky.edu

Objective— Angiotensin II (AngII) infusion into hyperlipidemic mice leads to the rapid formation of atherosclerotic lesions and abdominal aortic aneurysms (AAAs). To define the role of matrix metalloproteinases (MMPs) in the development of these vascular pathologies, we administered the broad-spectrum MMP inhibitor doxycycline to saline- and AngII-infused LDL receptor-/- mice.

Methods and Results— Mice were placed on a high-fat diet for 1 week before infusion with either saline or AngII (1000 ng · kg^-1 · min^-1) via osmotic pumps for 28 days. Doxycycline (30 mg · kg^-1 · d^-1) was administered in the drinking water to both saline- and AngII-infused mice. Administration of doxycycline did not significantly influence systolic blood pressure, serum cholesterol concentrations, or lipoprotein-cholesterol distribution. Doxycycline had no effect on the extent of atherosclerosis in saline- or AngII-infused mice. In contrast, doxycycline markedly reduced the incidence of AAA formation (86% vs 35%, AngII vs AngII+doxycycline, respectively; P<0.05), in addition to reducing aneurysm severity.

Conclusions— These data do not imply a role for MMPs in AngII-induced atherosclerosis but provide evidence consistent with a role in AngII-induced AAA formation.

Key Words: angiotensin • aneurysms • atherosclerosis • doxycycline • matrix metalloproteinases

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