ARTICLE: Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice

AUTHORS: Rosanne Rouf, Elena Gallo MacFarlane, Eiki TakimotoRahul Chaudhary, Varun Nagpal, Peter P. Rainer, Julia G. Bindman, Elizabeth E. Gerber, Djahida BedjaChristopher SchieferKaren L. Miller, Guangshuo Zhu, Loretha Myers, Nuria Amat-AlarconDong I. LeeNorimichi KoitabashiDaniel P. Judge, David A. Kass and Harry C. Dietz

JOURNAL: JCI Insight. 2017 Aug 3;2(15). pii: 91588. doi: 10.1172/jci.insight.91588. [Epub ahead of print]

Abstract

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.

For a link to the full article, click here: https://insight.jci.org/articles/view/91588

Link to abstract online: https://www.ncbi.nlm.nih.gov/pubmed/?term=Nonmyocyte+ERK1%2F2+signaling+contributes+to+load-induced+cardiomyopathy+in+Marfan+mice

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