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Background

Among desmosome gene mutations in arrhythmogenic cardiomyopathy (ACM), pathogenic desmoplakin (DSP) variants cause a distinctive cardiomyopathy with early and excessive cardiac fibrosis. Resident mesenchymal stromal cells (MSCs) are fibroblast-like progenitors that can develop into myofibroblasts responsible for fibrogenesis in most organs including hearts. We showed previously that pathogenic DSP variants in cardiac MSCs reduced wild-type (WT) DSP proteins and increased vimentin (VIM)-beclin-1 (BECN1) binding, leading to decreased BECN1 availability (BECN1 deficiency) and aggressive fibrosis after transforming growth factor-β1 (TGF-β1) treatment. Overexpression of exogenous plakophilin-2 (PKP2) has been proposed to treat ACM patients with PKP2 variants. DSP is a large protein and overexpressing large DSPs might not be efficient for clinical therapies.

Objective

To identify …