Comprehensive Myocardial Proteogenomics Profiling Reveals C/EBPα as the Key Factor in the Lipid Storage of ARVC

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is hereditary cardiomyopathy characterized by the fibro-fatty replacement of the myocardium. A small number of noncomprehensive profiling studies based on human cardiac tissues have been conducted and reported; consequently, ARVC's gene expression pattern characteristics remain largely undocumented. Our study applies large-scaled, quantitative proteomics based on TMT-labeled LC-MS/MS to analyze the left and right ventricular myocardium of four ARVC and four DCM explanted hearts to compare them with normal hearts. Our objective is to reveal the characteristic proteome pattern in ARVC compared with DCM as well as nondiseased heart. We also conducted the RNA sequencing of 10 right ventricles from ARVC hearts paired with four nondiseased donor hearts to validate the proteome results. In a manner similar to that of the well-defined DCM heart failure model, the ARVC model demonstrates the downregulation of mitochondrial function proteins and the effects of many heart failure regulators such as TGFB, RICTOR, and KDM5A. In addition, the inflammatory signaling, especially the complement system, was activated much more severely in ARVC than in DCM. Our most significant discovery was the lipid metabolism reprogramming of both ARVC ventricles in accordance with the upregulation of lipogenesis factors such as FABP4 and FASN. We identified the key upstream regulator of lipogenesis as C/EBP alpha. Transcriptome profiling verified the consistency with proteome alterations. This comprehensive proteogenomics profiling study reveals that an activation of C/EBP alpha, along with the upregulation of its lipogenesis targets, accounts for lipid storage and acts as a hallmark of ARVC.