PRODUCTION AND LOCALIZATION OF 92-KILODALTON GELATINASE IN ABDOMINAL AORTIC-ANEURYSMS - AN ELASTOLYTIC METALLOPROTEINASE EXPRESSED BY ANEURYSM-INFILTRATING MACROPHAGES
PRODUCTION AND LOCALIZATION OF 92-KILODALTON GELATINASE IN ABDOMINAL AORTIC-ANEURYSMS - AN ELASTOLYTIC METALLOPROTEINASE EXPRESSED BY ANEURYSM-INFILTRATING MACROPHAGES
复制标题
DOI：
10.1172/jci118037
复制
发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
PARKS, WC
中科院分区：
文献类型：
--
作者：
THOMPSON, RW;HOLMES, DR;PARKS, WC
腹主动脉瘤（AAA）的特征是弹性介质的破坏和降解，但涉及的弹性蛋白酶及其细胞来源尚不清楚。我们研究了92-kD明胶酶，一种弹性蛋白基质金属蛋白酶，是否参与AAA的病理生物学。明胶酶谱的条件培养基从正常，动脉粥样硬化闭塞性疾病（AOD），或AAA组织在器官培养显示，所有组织产生72 kD明胶酶。AOD和AAA文化也分泌92 kD明胶酶，但显着更多的酶从AAA组织释放。ELISA证实AAA组织释放的92-kD明胶酶比AOD组织多2倍，比正常主动脉多10倍。佛波酯诱导正常主动脉和AOD的92-kD明胶酶分泌增加5.3倍，AAA增加11.5倍。免疫组化结果显示，92-kD明胶酶在正常主动脉中未检测到，仅在AOD组织的新生内膜病变中偶见。然而，在所有AAA标本中，92-kD明胶酶很容易定位于中膜和外膜-中膜交界处的大量巨噬细胞。原位杂交证实了92-kD明胶酶mRNA的表达，由明胶酶浸润的巨噬细胞。这些结果表明，患病的主动脉组织分泌大量的明胶酶活性比正常主动脉主要是由于92-kD明胶酶的生产增加。此外，92-kD明胶酶的本地化巨噬细胞在受损的壁的腹主动脉瘤表明，这种弹性蛋白溶解性金属蛋白酶的慢性释放有助于细胞外基质降解在AAA。
Abdominal aortic aneurysms (AAA) are characterized by disruption and degradation of the elastic media, yet the elastolytic proteinases involved and their cellular sources are undefined. We examined if 92-kD gelatinase, an elastolytic matrix metalloproteinase, participates in the pathobiology of AAA. Gelatin zymography of conditioned medium from normal, atheroocclusive disease (AOD), or AAA tissues in organ culture showed that all tissues produced 72-kD gelatinase. AOD and AAA cultures also secreted 92-kD gelatinase, but significantly more enzyme was released from AAA tissues. ELISA confirmed that AAA tissues released similar to 2-fold more 92-kD gelatinase than AOD tissue and similar to 10-fold more than normal aorta. Phorbol ester induced a 5.3-fold increase in 92-kD gelatinase secretion by normal aorta and AOD and an 11.5-fold increase by AAA. By immunohistochemistry, 92-kD gelatinase was not detected in normal aorta and was only occasionally seen within the neointimal lesions of AOD tissue. In all AAA specimens, however, 92-kD gelatinase was readily localized to numerous macrophages in the media and at the adventitial-medial junction. The expression of 92-kD gelatinase mRNA by aneurysm-infiltrating macrophages was confirmed by in situ hybridization, These results demonstrate that diseased aortic tissues secrete greater amounts of gelatinolytic activity than normal aorta primarily due to increased production of 92-kD gelatinase. In addition, the localization of 92-kD gelatinase to macrophages in the damaged wall of aneurysmal aortas suggests that chronic release of this elastolytic metalloproteinase contributes to extracellular matrix degradation in AAA.