Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice.

Paradigms and Technologies
Therapeutic Approaches


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.


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


  • Animals
  • Anthracenes/ pharmacology
  • Anthracenes/ therapeutic use
  • Aorta/ pathology
  • Aortic Aneurysm/ metabolism
  • Aortic Aneurysm/ pathology
  • Aortic Aneurysm/ physiopathology
  • Aortic Aneurysm/ prevention & control
  • Diphenylamine/ analogs & derivatives
  • Diphenylamine/ pharmacology
  • Diphenylamine/ therapeutic use
  • Disease Models, Animal
  • Disease Progression
  • Enzyme Activation
  • Losartan/ pharmacology
  • Losartan/ therapeutic use
  • MAP Kinase Signaling System
  • Marfan Syndrome/ drug therapy
  • Marfan Syndrome/ metabolism
  • Marfan Syndrome/ pathology
  • Mice
  • Mitogen-Activated Protein Kinase 1/ antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1/ metabolism
  • Mitogen-Activated Protein Kinase 3/ antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3/ metabolism
  • Mitogen-Activated Protein Kinase 8/ antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8/ metabolism
  • Protein Kinase Inhibitors/ pharmacology
  • Protein Kinase Inhibitors/ therapeutic use
  • Smad2 Protein/ metabolism
  • Smad4 Protein/ deficiency
  • Smad4 Protein/ genetics
  • Sulfonamides/ pharmacology
  • Sulfonamides/ therapeutic use
  • Transforming Growth Factor beta/ antagonists & inhibitors
  • Transforming Growth Factor beta/ immunology
  • Transforming Growth Factor beta/ metabolism

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