Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice
| Autor: | Djahida Bedja, Nuria Amat-Alarcon, Norimichi Koitabashi, Eiki Takimoto, Elizabeth E. Gerber, Elena Gallo MacFarlane, Julia G. Bindman, Varun Nagpal, Dong I. Lee, Christopher Schiefer, Rahul Chaudhary, Guangshuo Zhu, Peter P. Rainer, Karen L. Miller, David A. Kass, Rosanne Rouf, Harry C. Dietz, Loretha Myers, Daniel P. Judge |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pressure overload MAPK/ERK pathway musculoskeletal diseases medicine.medical_specialty business.industry MEK inhibitor Cardiomyopathy General Medicine macromolecular substances 030204 cardiovascular system & hematology medicine.disease Angiotensin II 03 medical and health sciences Paracrine signalling 030104 developmental biology 0302 clinical medicine Endocrinology Fibrosis Internal medicine Medicine business Autocrine signalling Research Article |
| Zdroj: | JCI insight. 2(15) |
| ISSN: | 2379-3708 |
| Popis: | Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation. |
| Databáze: | OpenAIRE |
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