Matrix Metalloproteinase-9 Expression in Calcified Human Aortic Valves: A Histopathologic, Immunohistochemical, and Ultrastructural Study
Matrix Metalloproteinase-9 Expression in Calcified Human Aortic Valves: A Histopathologic, Immunohistochemical, and Ultrastructural Study
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DOI：
10.1097/pai.0000000000000144
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发表时间：
2016-02-01
影响因子：
1.6
通讯作者：
Mazzulla, Sergio
中科院分区：
文献类型：
--
作者：
Perrotta, Ida;Sciangula, Alfonso;Mazzulla, Sergio
钙化性主动脉瓣疾病（CAVD）的特征是细胞外基质（ECM）发生显著的定量和定性变化，最终导致瓣叶硬度增加和左心室流出道阻塞。越来越多的证据表明，ECM重塑不仅有助于瓣膜细胞功能障碍，而且还改变了某些细胞信号传导途径，负责疾病状态的起始和进展。基质金属蛋白酶（MMP），统称为基质蛋白，是已知在胚胎发育和疾病期间参与许多ECM重塑事件的酶家族。本研究的目的是评估MMP-9表达的变化是否可能参与CAVD的病理生理过程。为此，我们分析了19例因钙化性主动脉瓣狭窄接受主动脉瓣置换术的患者的病理瓣膜。显微镜下，瓣尖组织显示弥漫性纤维化、新生血管形成和异常ECM重塑，伴胶原蛋白分解和矿化。对覆盖和远离矿床的地区进行了Western印迹和免疫组织化学分析。蛋白质表达数据表明，在钙化病变区的MMP-9的显着上调。与这些观察结果一致，免疫组化表明，MMP-9蛋白几乎完全定位于矿化结节附近或周围，而在没有任何钙化的区域通常相当弱或不存在。我们的数据表明，MMP-9可能通过促进ECM的纤维化和前钙化重塑在CAVD中发挥关键作用。
The hallmarks of calcific aortic valve disease (CAVD) are the significant quantitative and qualitative changes that occur in the extracellular matrix (ECM), which ultimately lead to increased leaflet stiffness and obstruction of left ventricular outflow. Mounting evidence suggests that ECM remodeling not only contribute to valve cell dysfunction but also alter certain cell signaling pathways responsible for the initiation and progression of the disease state. Matrix metalloproteinases (MMPs), collectively called matrixins, are a family of enzymes known to participate in numerous ECM remodeling events during embryonic development and in disease. The aim of the present study was to evaluate whether changes in MMP-9 expression might be involved in the pathophysiology of CAVD. For this purpose, we have analyzed a total of 19 pathologic valves from patients who underwent aortic valve replacement for calcific aortic stenosis. Microscopically, the cusp tissue showed diffuse fibrosis, neovascularization, and abnormal ECM remodeling with collagen disorganization and mineralization. Western blot and immunohistochemical analyses have been performed on both the areas overlying and remote from the mineral deposits. Protein expression data evidenced a significant upregulation of MMP-9 in the calcified lesion area. Consistent with these observations, immunohistochemistry demonstrated that MMP-9 protein was almost exclusively localized near or around the mineralized nodules, whereas was generally quite weak or absent in areas devoid of any calcification. Our data suggest that MMP-9 may play a key role in CAVD probably by promoting the fibrotic and procalcific remodeling of the ECM.