Noncanonical TGF[beta] Signaling Contributes to Aortic Aneurysm Progression in Marfan Syndrome Mice

• Published in: Science (American Association for the Advancement of Science) Vol. 332; no. 6027; p. 358
• Main Authors: Holm, Tammy M, Habashi, Jennifer P, Doyle, Jefferson J, Bedja, Djahida, Chen, YiChun, Christel van Erp, Lindsay, Mark E, Kim, David, Schoenhoff, Florian, Cohn, Ronald D, Loeys, Bart L, Thomas, Craig J, Patnaik, Samarjit, Marugan, Juan J, Judge, Daniel P
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 15.04.2011
• Subjects: Aneurysms; Cellular biology; Coronary vessels; Cytokines; Inhibition; Rodents; Signal transduction
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1192149

Activation of transforming growth factor-β (TGF-β) signaling promotes the development of aortic aneurysms in the connective tissue disorder Marfan syndrome (MFS). Losartan, a drug that inhibits TGF-β signaling, is in clinical trials for this disorder. Like many cytokines, TGF-β activates multiple intracellular signaling pathways. In the context of aortic disease, TGF-β has been assumed to act through the "canonical" Smad pathway. Holm et al. (p. 358) and Habashi et al. (p. 361) now show that the "noncanonical" TGF-β pathway, which involves the signaling proteins ERK1/2, is the prominent driver of aortic disease in MFS mice and that it is this pathway through which losartan exerts its beneficial effects. Analysis of ERK1/2 activation status in MFS patients may help optimize losartan dosage, and drugs specifically targeting the noncanonical pathway may merit exploration as possible therapies for aortic aneurysms. 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. [PUBLICATION ABSTRACT]