Targeted p38 deletion arrested cardiac fibroblast responses in DCM mice, preventing cardiomyocyte remodeling and improving contractility.
Targeting p38-mediated fibroblast responses may be a potential therapeutic strategy for alleviating dilated cardiomyopathy severity.
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.
Bretherton et al. (Thu,) conducted a other in Dilated cardiomyopathy. Targeted p38 deletion was evaluated on Cardiomyocyte remodeling and contractility. Targeted p38 deletion arrested cardiac fibroblast responses in DCM mice, preventing cardiomyocyte remodeling and improving contractility.
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