Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms
Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms
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DOI：
10.1172/jci2182
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发表时间：
1998-12-01
影响因子：
15.9
通讯作者：
Thompson, RW
中科院分区：
文献类型：
--
作者：
Curci, JA;Liao, SX;Thompson, RW
弹性基质金属蛋白酶（MMP）与腹主动脉瘤（AAA）的发病机制有关，AAA是一种以慢性主动脉壁炎症和中层弹性蛋白破坏为特征的疾病。本研究的目的是确定是否人巨噬细胞弹性蛋白酶（HME; MMP-12）可能参与这种疾病。通过逆转录-聚合酶链反应，HME mRNA在AAA和动脉粥样硬化闭塞性疾病（AOD）组织（6/6）中得到一致证实，但在6个正常AAA中只有1个。免疫反应性蛋白对应于proHME和两个产品的细胞外加工存在于七个AAA组织提取物。从AAA组织中回收的总HME是正常主动脉的7倍（P < 0.001），并且提取的酶在体外表现出活性。原位杂交和免疫组化证实AAA组织中存在HME，但在正常或AOD标本中未检测到HME。重要的是，免疫反应性HME特异性定位于AAA组织中膜内的残余弹性蛋白片段，特别是邻近未扩张的正常主动脉的区域。在体外，MMP-12螯合的不溶性弹性蛋白的分数是2 - 5倍，比其他弹性蛋白酶在AAA组织中发现。因此，HME在AAA的退化主动脉中膜内的血管内浸润性巨噬细胞中显著表达，在那里它也与残留的弹性纤维碎片结合。因为弹性蛋白代表主动脉壁结构的关键组分和金属弹性蛋白酶的基质底物，所以HME在主动脉瘤的发病机制中可能具有直接和独特的作用。
Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The purpose of this study was to determine if human macrophage elastase (HME; MMP-12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosclerotic occlusive disease (AOD) tissues(six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two products of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than normal aorta (P < 0.001), and the extracted enzyme exhibited activity in vitro. Production of HME was demonstrated in the media of AAA tissues by in situ hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was specifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to fivefold greater than other elastases found in AAA tissue. Therefore, HME is prominently expressed by aneurysm-infiltrating macrophages within the degenerating aortic media of AAA, where it is also bound to residual elastic fiber fragments. Because elastin represents a critical component of aortic wall structure and a matrix substrate for metalloelastases, HME may have a direct and singular role in the pathogenesis of aortic aneurysms.