Seeking the Right Pathway

Science Signaling  19 Apr 2011:
Vol. 4, Issue 169, pp. ec112
DOI: 10.1126/scisignal.4169ec112

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. and Habashi et al. 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.

T. M. Holm, J. P. Habashi, J. J. Doyle, D. Bedja, Y. Chen, C. van Erp, M. E. Lindsay, D. Kim, F. Schoenhoff, R. D. Cohn, B. L. Loeys, C. J. Thomas, S. Patnaik, J. J. Marugan, D. P. Judge, H. C. Dietz, Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332, 358–361 (2011). [Abstract] [Full Text]

J. P. Habashi, J. J. Doyle, T. M. Holm, H. Aziz, F. Schoenhoff, D. Bedja, Y. Chen, A. N. Modiri, D. P. Judge, H. C. Dietz, Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 332, 361–365 (2011). [Abstract] [Full Text]