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Nature Medicine 11, 1330 - 1338 (2005)
Published online: 27 November 2005 | doi:10.1038/nm1335

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase

Koichi Yoshimura1, Hiroki Aoki1, Yasuhiro Ikeda1, Kozo Fujii1, Norio Akiyama2, Akira Furutani2, Yoshinobu Hoshii3, Nobuyuki Tanaka4, Romeo Ricci5, Tokuhiro Ishihara3, Kensuke Esato2, Kimikazu Hamano2 & Masunori Matsuzaki1,6

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.

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