Noncanonical TGFβ signaling contributes to aortic aneurysm progression in marfan syndrome mice

Tammy M. Holm, Jennifer Habashi, Jefferson Doyle, Djahida Bedja, YiChun Chen, Christel Van Erp, Mark E. Lindsay, David Kim, Florian Schoenhoff, Ronald D. Cohn, Bart L. Loeys, Craig J. Thomas, Samarjit Patnaik, Juan J. Marugan, Daniel P. Judge, Harry C Dietz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)358-361
Number of pages4
JournalScience
Volume332
Issue number6027
DOIs
StatePublished - Apr 15 2011

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Marfan Syndrome
Aortic Aneurysm
Transforming Growth Factors
Aortic Diseases
Phosphotransferases
Premature Mortality
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Growth
Aneurysm
Therapeutics
Clinical Trials

ASJC Scopus subject areas

  • General

Cite this

Noncanonical TGFβ signaling contributes to aortic aneurysm progression in marfan syndrome mice. / Holm, Tammy M.; Habashi, Jennifer; Doyle, Jefferson; Bedja, Djahida; Chen, YiChun; Van Erp, Christel; Lindsay, Mark E.; Kim, David; Schoenhoff, Florian; Cohn, Ronald D.; Loeys, Bart L.; Thomas, Craig J.; Patnaik, Samarjit; Marugan, Juan J.; Judge, Daniel P.; Dietz, Harry C.

In: Science, Vol. 332, No. 6027, 15.04.2011, p. 358-361.

Research output: Contribution to journalArticle

Holm, TM, Habashi, J, Doyle, J, Bedja, D, Chen, Y, Van Erp, C, Lindsay, ME, Kim, D, Schoenhoff, F, Cohn, RD, Loeys, BL, Thomas, CJ, Patnaik, S, Marugan, JJ, Judge, DP & Dietz, HC 2011, 'Noncanonical TGFβ signaling contributes to aortic aneurysm progression in marfan syndrome mice', Science, vol. 332, no. 6027, pp. 358-361. https://doi.org/10.1126/science.1192149
Holm, Tammy M. ; Habashi, Jennifer ; Doyle, Jefferson ; Bedja, Djahida ; Chen, YiChun ; Van Erp, Christel ; Lindsay, Mark E. ; Kim, David ; Schoenhoff, Florian ; Cohn, Ronald D. ; Loeys, Bart L. ; Thomas, Craig J. ; Patnaik, Samarjit ; Marugan, Juan J. ; Judge, Daniel P. ; Dietz, Harry C. / Noncanonical TGFβ signaling contributes to aortic aneurysm progression in marfan syndrome mice. In: Science. 2011 ; Vol. 332, No. 6027. pp. 358-361.
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