Discoidin Domain Receptor-1 Deficiency Attenuates Atherosclerotic Calcification and Smooth Muscle Cell-Mediated Mineralization
Discoidin Domain Receptor-1 Deficiency Attenuates Atherosclerotic Calcification and Smooth Muscle Cell-Mediated Mineralization
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DOI：
10.2353/ajpath.2009.080734
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发表时间：
2009-12-01
影响因子：
6
通讯作者：
Bendeck, Michelle P.
中科院分区：
文献类型：
--
作者：
Ahmad, Pamela J.;Trcka, Daniel;Bendeck, Michelle P.
内膜钙化是晚期动脉粥样硬化性疾病的特征之一，可预测冠状动脉事件风险增加2 - 8倍。I型胶原促进血管平滑肌细胞介导的钙化，尽管其发生的机制尚不清楚。盘状结构域受体1（DDR 1）是一种胶原蛋白受体，是动脉粥样硬化的关键介质。为了确定DDR 1是否参与内膜钙化，我们给雄性Ddr 1（-/-）;Ldlr（-/-）和Ddr 1（+/+）;Ldlr（-/-）小鼠喂食致动脉粥样硬化饮食6周、12周或24周。DDR 1缺乏显著降低了主动脉弓的钙含量，显微计算机断层扫描显示，在致动脉粥样硬化饮食24周后，羟基磷灰石沉积显著减少。钙化减少与巨噬细胞积聚和肿瘤坏死因子a染色减少相关，表明钙化减少部分是由于炎症减少。软骨形成标志物II型胶原、X型胶原和Sox-9在矿化灶内表达。血管平滑肌细胞的体外试验表明，DDR 1是细胞介导的基质钙化所必需的，DDR 1（+/+）平滑肌细胞表达更多的碱性磷酸酶活性，而DDR 1（-/-）平滑肌细胞表达的核苷酸焦磷酸酶磷酸二酯酶1（一种组织矿化抑制剂）mRNA水平升高。综上所述，我们的研究结果表明，DDR 1介导动脉粥样硬化钙化的重要机制。(Am J Pathol 2009，175：2686-2696; DOI：2009，175：2686-2696; DOI：10.2353/ajpath.2009.080734）
Intimal calcification is a feature of advanced atherosclerotic disease that predicts a two- to eightfold increase in the risk of coronary events. Type I collagen promotes vascular smooth muscle cell-mediated calcification, although the mechanism by which this occurs is unknown. The discoidin domain receptor 1 (DDR1) is a collagen receptor that is emerging as a critical mediator of atherosclerosis. To determine whether DDR1 is involved in intimal calcification, we fed male Ddr1(-/-);Ldlr(-/-) and Ddr1(+/+);Ldlr(-/-) mice an atherogenic diet for 6, 12, or 24 weeks. DDR1 deficiency significantly reduced the calcium content of the aortic arch, and microcomputed tomography demonstrated a significant decrease in hydroxyapatite deposition after 24 weeks of atherogenic diet. Reduced calcification was correlated with decreases in macrophage accumulation and tumor necrosis factor a staining, suggesting that the reduction in calcification was in part due to decreased inflammation. The chondrogenic markers type II collagen, type X collagen, and Sox-9 were expressed within the mineralized foci. An in vitro assay performed with vascular smooth muscle cells revealed that DDR1 was required for cell-mediated calcification of the matrix, and Ddr1(+/+) smooth muscle cells expressed more alkaline phosphatase activity, whereas Ddr1(-/-) smooth muscle cells expressed elevated levels of mRNA for nucleotide pyrophosphatase phosphodiesterase 1, an inhibitor of tissue mineralization. Taken together, our results demonstrate that DDR1 mediates an important mechanism for atherosclerotic calcification. (Am J Pathol 2009, 175:2686-2696; DOI: 2009, 175:2686-2696; DOI: 10.2353/ajpath.2009.080734)