Circ Heart Fail. 2026 Jun 5:e013966. doi: 10.1161/CIRCHEARTFAILURE.125.013966. Online ahead of print.
ABSTRACT
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene-positive ACM are caused by a desmosome protein mutation, with plakophilin-2 (Pkp2) mutations being the most common. We hypothesized that Pkp2-deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis.
METHODS: We developed transgenic mice that lack Pkp2 in cardiomyocytes (Pkp2-cKO), in EPDC (Pkp2-eKO), or in both cardiomyocyte and EPDC (Pkp2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Nonmyocyte populations were isolated 21 days posttamoxifen injection for single-cell RNA-sequencing. Immunohistochemistry, flow cytometry, quantitative reverse transcription polymerase chain reaction, and echocardiography were used to interrogate cardiac physiology and cellular composition.
RESULTS: We identified a population of epicardium-derived fibroblasts characterized by the expression of Ccl2, Ccl7, Thbs1, and Ptx3 that accumulated on Pkp2 deletion in both cardiomyocytes and EPDC. Pkp2 deletion in cardiomyocytes induced a moderate fibro-inflammatory EPDC phenotype, while deletion in EPDC did not elicit a pathological phenotype, suggesting cardiomyocyte involvement is necessary for ACM pathogenesis. Proinflammatory fibroblasts acquired the senescence-associated secretory phenotype, correlating with elevated senescence associated-βgal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in Pkp2-ceKO mice, which progresses from right to left ventricular predominance. Importantly, macrophages and B cells accumulate in both Pkp2-cKO and Pkp2-ceKO mice compared with controls. Although B-cell depletion delays the early inflammatory and fibrosis response, it did not alter end-stage cardiac physiology.
CONCLUSIONS: Pkp2 deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.
PMID:42246055 | DOI:10.1161/CIRCHEARTFAILURE.125.013966