on May 11, 2006
Published online before print May 11, 2006, doi: 10.1161/01.ATV.0000225807.76419.a7
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Submitted on November 22, 2005
Accepted on April 24, 2006
Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification
Xiao Qin ;
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.
* To whom correspondence should be addressed. 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.
Key words: artery • calcification • MMPs • doxycycline • GM6001 • rat
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