Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase
Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase
复制标题
DOI：
10.1038/nm1335
复制
发表时间：
2005-12-01
期刊：
影响因子：
82.9
通讯作者：
Matsuzaki, M
中科院分区：
文献类型：
--
作者：
Yoshimura, K;Aoki, H;Matsuzaki, M
腹主动脉瘤（AAA）是老年人中的常见疾病，当手术治疗不适用时，会导致主动脉进行性扩张和破裂，死亡率高。虽然AAA的非手术治疗是期待已久的，但由于其分子发病机制仍然难以捉摸，因此几乎没有选择。在这里，我们确定JNK作为近端信号分子在AAA的发病机制。人AAA组织显示高水平的磷酸化JNK。我们表明，JNK程序的基因表达模式在不同的细胞类型，协同增强细胞外基质的降解，同时抑制细胞外基质的生物合成酶。在两种小鼠模型中，体内选择性抑制JNK不仅阻止了AAA的发展，而且还引起了已建立的AAA的消退。因此，JNK促进AAA组织中异常的细胞外基质代谢，并可能代表治疗靶点。
Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.