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Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice
Rosanne Rouf1, Elena Gallo MacFarlane2, Eiki Takimoto1
1Division of Cardiology, Department of Medicine, and.
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.
Insights
Marfan syndrome (MFS) heart failure is linked to fibrillin-1 deficiency. Pressure overload causes MFS heart dysfunction via nonmyocyte ERK activation, suggesting ERK as a therapeutic target.
Area of Science:
- Cardiovascular Research
- Connective Tissue Disorders
- Molecular Cardiology
Background:
- Marfan syndrome (MFS) is an inherited connective tissue disorder.
- Fibrillin-1 deficiency is central to MFS pathogenesis.
- Heart failure is a primary cause of mortality in severe MFS cases.
Purpose of the Study:
- To investigate the mechanisms of cardiac decompensation in MFS under pressure overload.
- To identify key cellular pathways and potential therapeutic targets in MFS-related cardiomyopathy.
- To elucidate the role of fibrillin-1 in cardiac reserve during hemodynamic stress.
Main Methods:
- Utilized a mouse model of Marfan syndrome (Fbn1C1039G/+ mice).
- Induced pressure overload (PO) to simulate cardiac stress.
- Administered TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonists.
- Performed in situ analyses to examine cellular signaling pathways.
Main Results:
- MFS mice developed severe dilated cardiomyopathy, fibrosis, and myocyte enlargement under PO.
- Increased TGF-β signaling and ERK activation in nonmyocytes were observed in failing MFS hearts.
- Antagonism of TGF-β, AT1R, or ERK prevented load-induced cardiac decompensation in MFS mice.
- Identified an AT1R-dependent ERK activation axis in nonmyocytes driving TGF-β ligand expression.
Conclusions:
- Fibrillin-1 is crucial for maintaining cardiac reserve during hemodynamic stress.
- Nonmyocytes play a critical role in the pathogenesis of MFS-related cardiac decompensation.
- ERK signaling in nonmyocytes represents a promising therapeutic target for MFS cardiomyopathy.
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