Qin Xiao, Corriere Matthew A, Matrisian Lynn M, Guzman Raul J
Department of Surgery, Division of Vascular Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1510-6. doi: 10.1161/01.ATV.0000225807.76419.a7. Epub 2006 May 11.
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.
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.
These results suggest that MMPs are involved in aortic calcification, and inhibiting MMP activity could reduce calcium accumulation in the arterial wall.
动脉钙化与基质金属蛋白酶（MMP）介导的弹性蛋白降解有关。在本研究中，我们调查了抑制MMP活性是否能减少啮齿动物主动脉钙化模型中的钙积累。
首先通过给予维生素D3在雄性Sprague-Dawley大鼠中诱导主动脉钙化。强力霉素治疗可降低主动脉钙和磷的积累，并降低主动脉明胶酶水平；然而，它也阻止了与高剂量维生素D3相关的骨吸收。使用局部主动脉钙化的体内模型，全身强力霉素治疗可减少主动脉钙积累，而不影响血清钙水平，这表明强力霉素在动脉壁中有更特异性的作用。在器官培养中，强力霉素可限制由碱性磷酸酶和无机磷酸盐暴露引起的主动脉钙化。当使用MMPs的合成特异性抑制剂GM6001代替强力霉素时，也有类似效果。在体内，与对照组相比，向钙化动脉外膜周围递送GM6001可显著减少钙化。
这些结果表明MMPs参与主动脉钙化，抑制MMP活性可减少动脉壁中的钙积累。
