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/EBPα. Transcriptome profiling verified the
consistency with proteome alterations. This comprehensive proteogenomics
profiling study reveals that an activation of C/EBPα, along
with the upregulation of its lipogenesis targets, accounts for lipid
storage and acts as a hallmark of ARVC.