Elastin stabilization for treatment of abdominal aortic aneurysms
Elastin stabilization for treatment of abdominal aortic aneurysms
复制标题
DOI：
10.1161/circulationaha.106.672873
复制
发表时间：
2007-04-03
期刊：
影响因子：
37.8
通讯作者：
Vyavahare, Narendra R.
中科院分区：
文献类型：
--
作者：
Isenburg, Jason C.;Simionescu, Dan T.;Vyavahare, Narendra R.
背景：维持动脉弹性蛋白的完整性对于预防腹主动脉瘤（AAA）的发展至关重要。我们假设在体内用五烯丙基葡萄糖（一种结合弹性蛋白的多酚）稳定主动脉弹性蛋白会干扰AAA的发展。方法与结果：首先通过细胞毒性、弹性蛋白稳定性和PGG-弹性蛋白相互作用试验验证PGG治疗的安全性和有效性。在体内研究中，基于cacl2介导的主动脉损伤，在一个成熟的大鼠AAA模型中评估了PGG的疗效。在该模型中，在AAA开发过程中，PGG在2个不同的时间点被输送；与盐处理的对照主动脉相比，监测和评估pgg处理主动脉的主动脉直径、弹性蛋白完整性和其他病理方面。我们的研究结果表明，一次性给予无细胞毒性水平的PGG可抑制大鼠的弹性蛋白变性，减轻动脉瘤扩张，并阻碍AAA的发展，而不会干扰该模型的典型致病机制，即炎症、钙化和高金属蛋白酶活性。PGG特异性地与动脉弹性蛋白结合，在这样做的过程中，尽管存在来自炎症细胞的高水平蛋白酶，但仍保持弹性薄片的完整性。结论：在临床相关的动物模型中，皮膜周围给药PGG可阻碍AAA的发展。动脉瘤易发动脉段的主动脉弹性蛋白稳定为开发安全有效的AAAs治疗方法提供了巨大的潜力。
Background-Maintaining the integrity of arterial elastin is vital for the prevention of abdominal aortic aneurysm (AAA) development. We hypothesized that in vivo stabilization of aortic elastin with pentagalloyl glucose (PGG), an elastin-binding polyphenol, would interfere with AAA development.Methods and Results-Safety and efficacy of PGG treatment were first tested in vitro using cytotoxicity, elastin stability, and PGG-elastin interaction assays. For in vivo studies, the efficacy of PGG was evaluated within a well-established AAA model in rats on the basis of CaCl2-mediated aortic injury. With this model, PGG was delivered periadventitially at 2 separate time points during the course of AAA development; aortic diameter, elastin integrity, and other pathological aspects were monitored and evaluated in PGG-treated aortas compared with saline-treated control aortas. Our results show that a one-time periadventitial delivery of noncytotoxic levels of PGG inhibits elastin degeneration, attenuates aneurysmal expansion, and hinders AAA development in rats without interfering with the pathogenic mechanisms typical of this model, namely inflammation, calcification, and high metalloproteinase activities. PGG binds specifically to arterial elastin and, in doing so, preserves the integrity of elastic lamellae despite the presence of high levels of proteinases derived from inflammatory cells.Conclusions-Periadventitial administration of PGG hinders the development of AAA in a clinically relevant animal model. Stabilization of aortic elastin in aneurysm-prone arterial segments offers great potential toward the development of safe and effective therapies for AAAs.