Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.
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.
Yoshimura
Koichi
K
Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
Aoki
Hiroki
H
Ikeda
Yasuhiro
Y
Fujii
Kozo
K
Akiyama
Norio
N
Furutani
Akira
A
Hoshii
Yoshinobu
Y
Tanaka
Nobuyuki
N
Ricci
Romeo
R
Ishihara
Tokuhiro
T
Esato
Kensuke
K
Hamano
Kimikazu
K
Matsuzaki
Masunori
M
D000256:Adenoviridae; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001011:Aorta / Q000737:chemistry; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000517:prevention & control*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D014020:Tissue Extracts / Q000378:metabolism
D000873:Anthracenes; D016326:Extracellular Matrix Proteins; D014020:Tissue Extracts; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9