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

Abstract

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.

Identification of Potential Gene Interactions in Heart Failure Caused by Idiopathic Dilated Cardiomyopathy

“…eIF2α-ATF4-CHOP signaling is one of the major endoplasmic reticulum stress signaling pathways causing cardiac hypertrophy [ 32 ]. CDKN1A (p21) knockout mice (p21KO) were found to develop age-dependent cardiac hypertrophy and HF by 10 months of age [ 33 ]. The activation of CEBP, along with the upregulation of its lipogenesis targets, accounts for lipid storage and acts as a hallmark of arrhythmogenic right ventricular cardiomyopathy (another type of cardiomyopathy) [ 34 ].…”

Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy

“…This work has provided novel insights into molecular changes in human heart failure, implicating extracellular matrix remodelling, inflammatory signalling, oxidative stress, mitochondrial dysfunction, and branched chain amino acid metabolism as signature pathogenic changes [13][14][15] . The proteomic studies usually used small numbers, infrequently more than one aetiology, and without matching across age, gender, and BMI 13,14,[16][17][18][19][20] . Further, a more extensive understanding as to whether upstream perturbations are propagated downstream via translation to the protein level, and further via enzymatic processing to the metabolite level, are required.…”

Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice

“…Interestingly, Pitx2 was the only gene in common between the set of 66 differentially expressed genes in the MuRF1−/− hearts and the set of 45 differentially expressed genes in the MuRF1 Tg + hearts. Pitx2 expression was induced in RV in mice lacking MuRF1 and was repressed in response to MuRF1 overexpression, suggesting an exquisite sensitivity of this gene to levels of MuRF1.The Fatty Acid Synthase ( FASN aka C93 ) gene was associated with lipid metabolism reprogramming in arrhythmogenic RV cardiomyopathy [ 65 ], while hypoxia has been associated with FASN-dependent free fatty acid production [ 66 – 68 ]. Lastly, the RAB3 GTPase Activating Protein Catalytic Subunit 1 ( Rab3gap1 ) has been associated with cardiovascular risk (total cholesterol and HDL) by GWAS association in Framingham Heart Studies [ 69 ], with Rab3gap1 loci having associations with an increased risk of SCD [ 70 ].…”