Matrix metalloproteinase inhibition attenuates aortic calcification

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 D-3. 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 D-3. 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.