Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms
Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms
复制标题
DOI：
10.1172/jci8931
复制
发表时间：
2000-06-01
影响因子：
15.9
通讯作者：
Thompson, RW
中科院分区：
文献类型：
--
作者：
Pyo, R;Lee, JK;Thompson, RW
腹主动脉瘤是一种危及生命的疾病，其特征是慢性炎症、细胞外基质的破坏性重塑和基质金属蛋白酶（MMPs）的局部表达增加。92-kD明胶酶（MMP-9）和巨噬细胞弹性酶（MMP-12）均与此病有关，但尚不清楚两者在动脉瘤变性中是否必要。我们在此表明，小鼠主动脉的短暂弹性蛋白酶灌注导致动脉瘤发育延迟，这与跨壁单核炎症、几种弹性溶解性MMPs的局部产生增加以及弹性片层的进行性破坏有关。弹性酶诱导的动脉瘤变性可以通过非选择性MMP抑制剂（强力霉素）和靶向MMP-9基因破坏来抑制，但不能通过孤立的MMP-12缺乏来抑制。野生型小鼠的骨髓移植阻止了mmp -9缺陷动物的动脉瘤抗性表型，野生型小鼠在从mmp -9缺陷供体移植后获得了动脉瘤抗性。这些结果表明，炎症细胞表达MMP-9在主动脉瘤疾病的实验模型中起着关键作用，提示针对MMP-9的治疗策略可能会限制小腹主动脉瘤的生长。
Abdominal aortic aneurysms represent a Life-threatening condition characterized by chronic inflammation, destructive remodeling of the extracellular matrix, and increased local expression of matrix metalloproteinases (MMPs). Both 92-kD gelatinase (MMP-9) and macrophage elastase (MMP-12) have been implicated in this disease, but it is not known if either is necessary in aneurysmal degeneration. We show here that transient elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12. Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors. These results demonstrate that inflammatory cell expression of MMP-9 plays a critical role in an experimental model of aortic aneurysm disease, suggesting that therapeutic strategies targeting MMP-9 may limit the growth of small abdominal aortic aneurysms.