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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}

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