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

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Abstract

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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Figure 1: Expression and phosphorylation of MAP kinases and MMPs in human AAA.
Figure 2: The role of JNK in secretion of MMPs.
Figure 3: Prevention of the development of AAA by JNK inhibition.
Figure 4: The role of ECM biosynthesis in AAA development.
Figure 5: Regression of AAA by JNK inhibition.

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Acknowledgements

We thank D. Boyle and G.S. Firestein for suggestions, S. Saito, M. Oishi and T. Hozawa for technical assistance and E.O. Weinberg, H. Suzuki and H. Oda for critical reading. This work was supported in part by Grant-in-aid for Scientific Research (KAKENHI 12770651, 14657284 and 17591337 (to K.Y.), 12670673, 12204081, 14370229 and 16390365 (to H.A.), 12770344 (to K.F.) and 16209026 (to M.M.)) from MEXT Japan, Japan Heart Foundation/Zeria Pharmaceutical Grant for Research on Cardiovascular Disease (to H.A.), New Frontier Project from Yamaguchi University (to H.A. and K.Y.) and a Grant from Sankyo Company for the Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine.

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Correspondence to Hiroki Aoki.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression and effect of JNK activity modifiers in VSMCs. (PDF 185 kb)

Supplementary Fig. 2

Definition of JNK Dependence Index. (PDF 170 kb)

Supplementary Fig. 3

Phosphorylated JNK in control, AAA and AOD tissues. (PDF 200 kb)

Supplementary Fig. 4

The role of JNK in expression and secretion of MMPs. (PDF 236 kb)

Supplementary Fig. 5

Determination of aortic internal diameter in live mice by ultrasonography. (PDF 293 kb)

Supplementary Table

The entire list of JNK-regulated genes. (PDF 479 kb)

Supplementary Methods (PDF 30 kb)

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Yoshimura, K., Aoki, H., Ikeda, Y. et al. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med 11, 1330–1338 (2005) doi:10.1038/nm1335

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