Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.
Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaCl(2), which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECM biosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl(2)-induced AAA. Furthermore, SP600125 treatment after the establishment of AAA caused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.
Yoshimura
Koichi
K
Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan. yoshimko@yamaguchi-u.ac.jp
Aoki
Hiroki
H
Ikeda
Yasuhiro
Y
Furutani
Akira
A
Hamano
Kimikazu
K
Matsuzaki
Masunori
M
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases