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Preventing hypocontractility-induced fibroblast expansion alleviates dilated cardiomyopathy
Ross C Bretherton1,2,3, Isabella M Reichardt1,2,3, Kristin A Zabrecky2,3,4
1Department of Bioengineering, University of Washington, Seattle, WA, USA.
Insights
Inherited dilated cardiomyopathy (DCM) involves hypocontractile cardiomyocytes. Cardiac fibroblasts expand and stiffen the heart before myocyte remodeling, but targeting p38 can prevent this, improving contractility.
Area of Science:
- Cardiovascular Biology
- Cardiac Fibrosis
- Sarcomere Biology
Background:
- Inherited dilated cardiomyopathy (DCM) is characterized by cardiomyocyte hypocontractility.
- The role of cardiac fibroblasts in modifying DCM phenotypes is not well understood, despite their association with disease severity through fibrosis.
- Fibroblast activation and subsequent myocardial fibrosis are key drivers of heart failure progression.
Purpose of the Study:
- To investigate the role of cardiac fibroblasts in the pathogenesis of DCM.
- To determine if fibroblast expansion and activation precede or follow cardiomyocyte remodeling in DCM.
- To explore the potential of targeting fibroblast responses as a therapeutic strategy for DCM.
Main Methods:
- Generation of a mouse model expressing a hypocontractility-linked sarcomeric variant.
- Analysis of cardiac fibroblast proliferation, activation, and collagen organization.
- Assessment of myocyte remodeling and cardiac function.
- Pharmacological or genetic inhibition of p38 signaling in cardiac fibroblasts.
Main Results:
- Expression of the sarcomeric variant induced cardiac fibroblast expansion and hyperproliferation, forming mechanosensitized states prior to myocyte remodeling.
- Fibroblast activation led to collagen reorganization and myocardial stiffening without initial fibrotic deposition.
- Increased matrix-integrin interactions and focal adhesion tension were observed in fibroblasts.
- Targeted deletion of p38 in fibroblasts prevented myocyte remodeling and improved cardiac contractility.
- p38-mediated fibroblast responses were identified as critical regulators of DCM severity.
Conclusions:
- Cardiac fibroblast expansion and activation are early events in DCM pathogenesis, preceding myocyte remodeling.
- p38 signaling in fibroblasts is essential for driving DCM progression and severity.
- Targeting p38-mediated fibroblast responses represents a promising therapeutic avenue for inherited dilated cardiomyopathy.
Abstract:
Cardiomyocyte hypocontractility underlies inherited dilated cardiomyopathy (DCM). Yet, whether fibroblasts modify DCM phenotypes remains unclear despite their regulation of fibrosis, which strongly predicts disease severity. Expression of a hypocontractility-linked sarcomeric variant in mice triggered cardiac fibroblast expansion from the de novo formation of hyperproliferative mechanosensitized fibroblast states, which occurred prior to eccentric myocyte remodeling. Initially, this fibroblast response reorganized fibrillar collagen and stiffened the myocardium, albeit without depositing fibrotic tissue. These adaptations coincided with heightened matrix-integrin receptor interactions and diastolic tension sensation at focal adhesions within fibroblasts. Targeted p38 deletion arrested these cardiac fibroblast responses in DCM mice, which prevented cardiomyocyte remodeling and improved contractility. p38-mediated fibroblast responses were essential regulators of DCM severity, marking a potential cellular target for therapeutic intervention.
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