Annabi Borhane, Shédid Daniel, Ghosn Pierre, Kenigsberg Rhoda L, Desrosiers Richard R, Bojanowski Michel W, Beaulieu Edith, Nassif Edgar, Moumdjian Robert, Béliveau Richard
Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine-UQAM, Montreal, PQ, Canada.
J Vasc Surg. 2002 Mar;35(3):539-46. doi: 10.1067/mva.2002.121124.
The increased synthesis of matrix metalloproteinases (MMPs) by aortic smooth muscle cells (SMCs) is thought to be involved in the etiopathogenesis of abdominal aortic aneurysms (AAAs), but the functional regulation and the activation states of these MMPs remain unclear. In this study, we assessed the expression levels and the functional regulation of several MMPs in the pathogenesis of AAAs.
Human healthy aorta and AAA specimens were homogenized, and the proteolytic activities of MMP-2 and MMP-9 and of the macrophage metalloelastase (MMP-12) were assessed with zymography. Protein expression of MMP-1, MMP-12, membrane-type 1 MMP (MT1-MMP), tissue inhibitor of MMP 1 (TIMP-1), TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed with electrophoresis on sodium dodecyl sulfate gels and immunoblotting.
MMP-1, MMP-9, and MMP-12 zymogen levels and proteolytic activities were increased in AAAs when compared with healthy aorta. A severe reduction in alpha-actin--positive vascular SMCs was observed in all the AAA specimens and was correlated with an increase in TIMP-3 but not TIMP-1 or TIMP-2 potential activities. Although pro--MMP-2 activity was decreased, the extent of activated MMP-2 remained unaffected in the AAAs. In accordance with this result, a highly activated MT1-MMP form was also observed in AAAs.
These data suggest that chronic aortic wall inflammation is mediated by macrophage infiltration, which may account for the destruction of medial elastin, as reflected by SMC down regulation, through increased levels of active MMP-1 and MMP-12. Moreover, altered MT1-MMP proteolytic turnover and differential regulation of TIMP expression in AAAs suggest that tight regulatory mechanisms are involved in the molecular regulation of MMP activation processes in the pathogenesis of AAAs.
主动脉平滑肌细胞（SMC）中基质金属蛋白酶（MMP）合成增加被认为与腹主动脉瘤（AAA）的发病机制有关，但这些MMP的功能调节和激活状态仍不清楚。在本研究中，我们评估了几种MMP在AAA发病机制中的表达水平和功能调节。
将人类健康主动脉和AAA标本匀浆，采用酶谱法评估MMP-2、MMP-9和巨噬细胞金属弹性蛋白酶（MMP-12）的蛋白水解活性。通过十二烷基硫酸钠凝胶电泳和免疫印迹分析MMP-1、MMP-12、膜型1 MMP（MT1-MMP）、MMP组织抑制剂1（TIMP-1）、TIMP-2、TIMP-3、α-肌动蛋白和β-肌动蛋白的蛋白表达。
与健康主动脉相比，AAA中MMP-1、MMP-9和MMP-12酶原水平及蛋白水解活性增加。在所有AAA标本中均观察到α-肌动蛋白阳性血管SMC严重减少，且与TIMP-3活性增加相关，但与TIMP-1或TIMP-2潜在活性无关。尽管前MMP-2活性降低，但AAA中活化的MMP-2程度未受影响。根据这一结果，在AAA中也观察到高度活化的MT1-MMP形式。
这些数据表明，慢性主动脉壁炎症由巨噬细胞浸润介导，这可能解释了中膜弹性蛋白的破坏，如SMC下调所反映的，这是通过活性MMP-1和MMP-12水平增加实现的。此外，AAA中MT1-MMP蛋白水解周转的改变和TIMP表达的差异调节表明，紧密的调节机制参与了AAA发病机制中MMP激活过程的分子调节。
