Allaire E, Forough R, Clowes M, Starcher B, Clowes A W
Service de Chirurgie Vasculaire, Hôpital H. Mondor, 94010 Créteil, France.
J Clin Invest. 1998 Oct 1;102(7):1413-20. doi: 10.1172/JCI2909.
Although matrix metalloproteinases (MMPs) are expressed in abundance in arterial aneurysms, their contribution to arterial wall degeneration, dilation, and rupture has not been determined. We investigated MMP function in a rat model of aneurysm associated with arterial dilation, elastin loss, medial invasion by mononuclear inflammatory cells, and MMP upregulation. Rupture was correlated with increased gelatinase B (MMP-9) and activated gelatinase A (MMP-2). Syngeneic rat smooth muscle cells retrovirally transfected with tissue inhibitor of matrix metalloproteinases (TIMP)-1 cDNA (LTSN) or with the vector alone as a control (LXSN) were seeded onto the luminal surface of the vessels. The seeding of LTSN cells resulted in TIMP-1 local overexpression. The seeding with LTSN cells, but not LXSN cells, decreased MMP-9, activated MMP-2 and 28-kD caseinase and elastase activity, preserved elastin in the media, and prevented aneurysmal degeneration and rupture. We conclude that MMP overexpression is responsible for aneurysmal degeneration and rupture in this rat model and that local pharmacological blockade might be a reasonable strategy for controlling the formation of aneurysms in humans.
尽管基质金属蛋白酶（MMPs）在动脉动脉瘤中大量表达，但其对动脉壁退变、扩张和破裂的作用尚未明确。我们在一个与动脉扩张、弹性蛋白丢失、单核炎性细胞向中膜浸润以及MMP上调相关的动脉瘤大鼠模型中研究了MMP的功能。破裂与明胶酶B（MMP - 9）和活化的明胶酶A（MMP - 2）增加相关。将用基质金属蛋白酶组织抑制剂（TIMP）-1 cDNA逆转录病毒转染的同基因大鼠平滑肌细胞（LTSN）或仅用载体作为对照（LXSN）接种到血管腔表面。接种LTSN细胞导致TIMP - 1局部过表达。接种LTSN细胞而非LXSN细胞可降低MMP - 9、活化的MMP - 2以及28-kD酪蛋白酶和弹性蛋白酶活性，保留中膜的弹性蛋白，并防止动脉瘤退变和破裂。我们得出结论，在这个大鼠模型中MMP过表达是动脉瘤退变和破裂的原因，并且局部药物阻断可能是控制人类动脉瘤形成的合理策略。
