Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 332 (6027): 358-361

Copyright © 2011 by the American Association for the Advancement of Science

Noncanonical TGFβ Signaling Contributes to Aortic Aneurysm Progression in Marfan Syndrome Mice

Tammy M. Holm,1,* Jennifer P. Habashi,1,2,* Jefferson J. Doyle,1,* Djahida Bedja,3 YiChun Chen,1 Christel van Erp,1 Mark E. Lindsay,1,2 David Kim,1 Florian Schoenhoff,1 Ronald D. Cohn,1,2 Bart L. Loeys,4 Craig J. Thomas,5 Samarjit Patnaik,5 Juan J. Marugan,5 Daniel P. Judge,6 Harry C. Dietz1,2,6,{dagger}

Abstract: Transforming growth factor–β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal–regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase–1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.

1 Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Centre for Medical Genetics, Ghent University, 9000 Ghent, Belgium.
5 National Institutes of Health Chemical Genomics Center, Rockville, MD 20850, USA.
6 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: hdietz{at}jhmi.edu.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
TGF-{beta}-activated Kinase 1 (Tak1) Mediates Agonist-induced Smad Activation and Linker Region Phosphorylation in Embryonic Craniofacial Neural Crest-derived Cells.
K. Yumoto, P. S. Thomas, J. Lane, K. Matsuzaki, M. Inagaki, J. Ninomiya-Tsuji, G. J. Scott, M. K. Ray, M. Ishii, R. Maxson, et al. (2013)
J. Biol. Chem. 288, 13467-13480
   Abstract »    Full Text »    PDF »
Angiotensin-Converting Enzyme-Induced Activation of Local Angiotensin Signaling Is Required for Ascending Aortic Aneurysms in Fibulin-4-Deficient Mice.
J. Huang, Y. Yamashiro, C. L. Papke, Y. Ikeda, Y. Lin, M. Patel, T. Inagami, V. P. Le, J. E. Wagenseil, and H. Yanagisawa (2013)
Science Translational Medicine 5, 183ra58
   Abstract »    Full Text »    PDF »
Latent TGF-{beta} binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5.
K. Noda, B. Dabovic, K. Takagi, T. Inoue, M. Horiguchi, M. Hirai, Y. Fujikawa, T. O. Akama, K. Kusumoto, L. Zilberberg, et al. (2013)
PNAS 110, 2852-2857
   Abstract »    Full Text »    PDF »
Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice.
G. Guo, B. Munoz-Garcia, C.-E. Ott, J. Grunhagen, S. A. Mousa, A. Pletschacher, Y. von Kodolitsch, P. Knaus, and P. N. Robinson (2013)
Hum. Mol. Genet. 22, 433-443
   Abstract »    Full Text »    PDF »
The fibrillin-1 gene: unlocking new therapeutic pathways in cardiovascular disease.
P. M. Barrett and E. J. Topol (2013)
Heart 99, 83-90
   Abstract »    Full Text »    PDF »
TGF{beta}RIIb Mutations Trigger Aortic Aneurysm Pathogenesis by Altering Transforming Growth Factor {beta}2 Signal Transduction.
K. J. Bee, D. C. Wilkes, R. B. Devereux, C. T. Basson, and C. J. Hatcher (2012)
Circ Cardiovasc Genet 5, 621-629
   Abstract »    Full Text »    PDF »
CCN2/CTGF increases expression of miR-302 microRNAs, which target the TGF{beta} type II receptor with implications for nephropathic cell phenotypes.
N. Faherty, S. P. Curran, H. O'Donovan, F. Martin, C. Godson, D. P. Brazil, and J. K. Crean (2012)
J. Cell Sci. 125, 5621-5629
   Abstract »    Full Text »    PDF »
Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta.
Z. Zhang, M. Wang, X.-H. Fan, J.-H. Chen, Y.-Y. Guan, and Y.-B. Tang (2012)
Circ. Res. 111, 1137-1146
   Abstract »    Full Text »    PDF »
Modulation of Transforming Growth Factor-{beta} Signaling and Extracellular Matrix Production in Myxomatous Mitral Valves by Angiotensin II Receptor Blockers.
A. Geirsson, M. Singh, R. Ali, H. Abbas, W. Li, J. A. Sanchez, S. Hashim, and G. Tellides (2012)
Circulation 126, S189-S197
   Abstract »    Full Text »    PDF »
MMP-2 Regulates Erk1/2 Phosphorylation and Aortic Dilatation in Marfan Syndrome.
W. Xiong, T. Meisinger, R. Knispel, J. M. Worth, and B. T. Baxter (2012)
Circ. Res. 110, e92-e101
   Abstract »    Full Text »    PDF »
Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-{beta} signaling.
H. Wei, D. Bedja, N. Koitabashi, D. Xing, J. Chen, K. Fox-Talbot, R. Rouf, S. Chen, C. Steenbergen, J. W. Harmon, et al. (2012)
PNAS 109, E841-E850
   Abstract »    Full Text »    PDF »
Interplay Between Heart and Skeletal Muscle Disease in Heart Failure: The 2011 George E. Brown Memorial Lecture.
E. M. McNally and J. A. Goldstein (2012)
Circ. Res. 110, 749-754
   Abstract »    Full Text »    PDF »
Top Advances in Functional Genomics and Translational Biology for 2011.
A. S. Barth, J. F. Ferguson, and K. Musunuru (2012)
Circ Cardiovasc Genet 5, 143-145
   Full Text »    PDF »
Fibroblast Growth Factor 9 (FGF9)-Pituitary Homeobox 2 (PITX2) Pathway Mediates Transforming Growth Factor {beta} (TGF{beta}) Signaling to Regulate Cell Proliferation in Palatal Mesenchyme during Mouse Palatogenesis.
J.-i. Iwata, L. Tung, M. Urata, J. G. Hacia, R. Pelikan, A. Suzuki, L. Ramenzoni, O. Chaudhry, C. Parada, P. A. Sanchez-Lara, et al. (2012)
J. Biol. Chem. 287, 2353-2363
   Abstract »    Full Text »    PDF »
TGF-{beta}1 mediates sirolimus and cyclosporine A-induced alteration of barrier function in renal epithelial cells via a noncanonical ERK1/2 signaling pathway.
N. Martin-Martin, C. Slattery, T. McMorrow, and M. P. Ryan (2011)
Am J Physiol Renal Physiol 301, F1281-F1292
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882