Cardiomyocyte-specific Pkp2 knockout in mice caused progressive, region-specific protein remodeling, with temporal changes occurring earlier in the right ventricle than the left ventricle.
Time-resolved proteomics in Pkp2-deficient mice reveals that global protein remodeling occurs earlier in the right ventricle than the left ventricle, providing a molecular framework for early arrhythmogenic cardiomyopathy development.
Abstract Introduction Arrhythmogenic cardiomyopathy (ACM) is an inheritable cardiac disorder that presents as a progressive, sometimes asymmetric, loss of myocardial mass with fibrofatty replacement. Most familial cases of ACM are due to pathogenic variants in the Pkp2 gene, which encodes the desmosomal protein plakophilin-2. Pkp2-ACM is marked by an initial, highly arrhythmogenic but otherwise subclinical "concealed phase", followed by an arrhythmogenic cardiomyopathy of right ventricular (RV)-predominance which can progress to a biventricular cardiomyopathy and, ultimately, end-stage heart failure. The molecular underpinnings of disease progression, both temporally and across the ventricles, remain incompletely understood. In this study, we applied time-resolved proteomics to map region-specific proteome remodeling in Pkp2-deficient mouse hearts. Methods We used a cardiomyocyte-specific, tamoxifen (TAM)-inducible Pkp2 knockout mouse (Pkp2cKO), which recapitulates key features of Pkp2-ACM within a compressed timeline. RV and left ventricle (LV) tissues were collected 7–21 days post-TAM induction. High-resolution mass spectrometry quantified 5,300 proteins from formalin-fixed, paraffin-embedded (FFPE) samples (72 total), including TAM-negative controls. Results We observed that Pkp2 levels progressively declined over time in both ventricles, accompanied by reductions in other desmosomal proteins. Although desmosomal proteins decreased synchronously in LV and RV, broader proteomic remodeling showed clear regional asymmetry. Principal component analysis indicated that time was a major source of RV-LV disparity in the dataset, with temporal changes in protein abundance occurring earlier in the RV (14 days post-TAM) than in the LV (17-21 days post-TAM). These temporal profiles resolve the order in which protein remodeling occurs. Conclusions Time-resolved proteomics in Pkp2-deficient hearts reveals progressive, region-specific protein remodeling, with RV tissue exhibiting earlier global deviations than LV tissue. These data provide a molecular framework for understanding temporal and spatial differences during early ACM development.
Achter et al. (Fri,) conducted a other in Arrhythmogenic cardiomyopathy (ACM) (n=72). Cardiomyocyte-specific Pkp2 knockout vs. TAM-negative controls was evaluated on Region-specific proteome remodeling. Cardiomyocyte-specific Pkp2 knockout in mice caused progressive, region-specific protein remodeling, with temporal changes occurring earlier in the right ventricle than the left ventricle.