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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1510.)
© 2006 American Heart Association, Inc.

Vascular Biology

Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification

Xiao Qin; Matthew A. Corriere; Lynn M. Matrisian; Raul J. Guzman

From the Department of Surgery, Division of Vascular Surgery, Vanderbilt University Medical Center (X.Q., M.A.C., R.J.G.), Nashville, Tenn; Guangxi Medical University First Affiliated Hospital, China (X.Q.); and the Departments of Cell and Developmental Biology (R.J.G.) and Cancer Biology (L.M.M.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Raul J. Guzman, MD, Division of Vascular Surgery, Vanderbilt University Hospital, D-5237, MCN Building, 1161 21st Ave S, Nashville, TN 37232. E-mail raul.guzman{at}vanderbilt.edu

Objective— Arterial calcification has been associated with matrix metalloproteinase (MMP)–mediated elastin degradation. In this study, we investigated whether inhibiting MMP activity could reduce calcium accumulation in rodent models of aortic calcification.

Methods and Results— Aortic calcification was first induced in male Sprague-Dawley rats by administration of vitamin D₃. Treatment with doxycycline decreased aortic calcium and phosphorus accumulation, and it reduced aortic gelatinase levels; however, it also prevented the bone resorption associated with high doses of vitamin D₃. Using an in vivo model of localized aortic calcification, systemic doxycycline treatment reduced aortic calcium accumulation without affecting serum calcium levels, suggesting a more specific effect of doxycycline in the arterial wall. In organ culture, doxycycline limited aortic calcification caused by exposure to alkaline phosphatase and inorganic phosphate. When GM6001, a synthetic and specific inhibitor of MMPs, was used instead of doxycycline, it had a similar effect. In vivo, periadventitial delivery of GM6001 to calcifying arteries significantly reduced calcification compared with controls.

Conclusions— These results suggest that MMPs are involved in aortic calcification, and inhibiting MMP activity could reduce calcium accumulation in the arterial wall.

Arterial calcification is associated with MMP-mediated matrix degradation. Inhibiting MMP activity with doxycycline or the synthetic MMP-inhibitor GM6001 prevents calcium accumulation in the arterial wall.

Key Words: artery • calcification • MMPs • doxycycline • GM6001 • rat

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