Inhibition of Aortic Elastolysis by Adenoviral Gene Transfer of the Tissue-Inhibitor of Matrixmetalloproteinase-1 in Fibrillin-1 Deficient Gene Targeted Mice

马凡综合征的血管成分以主动脉壁平滑肌细胞中基质金属蛋白酶(MMPs)活性异常增高为特征。这组酶导致主动脉中膜弹性溶解，导致血管壁进行性失稳。因此，危及生命的主动脉瘤和主动脉夹层可能发生在马凡综合征患者的生命早期。以纯合子纤维蛋白-1缺陷基因为靶标的小鼠代表了公认的马凡氏综合症的小动物模型。与马凡综合征患者相似，该模型显示主动脉壁平滑肌细胞中的基质金属蛋白酶活性增加，弹性纤维断裂程度随年龄增加而增加。利用该模型，本项目的目的是通过体外基因转移降低移植的主动脉中基质金属蛋白酶活性，从而导致基质金属蛋白酶组织抑制因子1(TIMP-1)的过度表达。将基因靶向供体动物移植到基因靶向受体动物的肾下主动脉6周后，通过形态计量学、组织学和酶谱技术对移植物的形态、组织学和酶谱进行评估，以确定是否可以减弱S中膜血管的弹性溶解。这一概念的证明可能会首次允许马凡综合征血管成分的因果治疗选择。

The vascular component of the Marfan syndrome is characterized by an abnormal increase in activity of matrix-metalloproteinases (MMPs) in smooth muscle cells of the aortic wall. This group of enzymes causes elastolysis in the aortic media resulting in a progressive destabilization of the vessel wall. Therefore, life-threatening aortic aneurysms and aortic dissections may develop early in life of patients with Marfan syndrome. The homozygote Fibrillin-1 deficient gene targeted mouse represents an accepted small animal model for the Marfan syndrome. Similar to patients with Marfan syndrome, this model expresses an increased MMP activity in smooth muscle cells of the aortic wall with an age dependent increase in fragmentation of elastic fibers. Using this model, aim of the project is the reduction of MMP activity in transplanted aortic grafts by in vitro gene transfer resulting in overexpression of the tissue inhibitor of matrix-metalloproteinase 1 (TIMP-1). Up to six weeks after infrarenal aortic transplantation of gene targeted donor animals into gene targeted recipient animals, the grafts will be evaluated by morphometrical, histological, and zymographical techniques, whether the elastolysis in the vessel¿s media can be attenuated. Proof of this concept may allow a causal treatment option of the vascular component of the Marfan syndrome for the first time.