To identify cellular and molecular mechanisms driving arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) and test whether cardiomyocyte-specific inhibition of p53 signaling can serve as a therapeutic strategy.
Performed single-nucleus RNA sequencing on left ventricles from transgenic mice overexpressing human wild-type or S358L mutant TMEM43 across early (5 weeks), mild (10 weeks), and severe (16 weeks) disease stages (n=6; 3 pooled hearts/time point/genotype).
Analyzed DNA damage response and p53 signaling markers by Western blot and RT-qPCR in mouse myocardium and in human right and left ventricular tissue from patients with ARVC5, dilated cardiomyopathy, and noncardiomyopathy controls.
Mutant TMEM43 mouse hearts showed a 42% reduction in cardiomyocyte nuclei and a 2-fold expansion of fibroblasts and myeloid cells by 16 weeks, driven by early DNA damage response and p53 pathway activation.
Human ARVC5 right and left ventricular myocardium exhibited consistent upregulation of the DNA damage response and p53 transcriptional signature relative to control and dilated cardiomyopathy myocardium.
Cardiomyocyte-specific p53 inhibition with AAV-GSE56 increased left ventricular ejection fraction and tricuspid annular plane systolic excursion, reduced left ventricular end-diastolic volume, narrowed QRS duration, and increased QRS amplitude.
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Implication
Preclinical study demonstrates that cardiomyocyte-specific p53 inhibition improves cardiac function in ARVC5 mice, suggesting p53 is a therapeutic target.
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