A common gene signature of the right ventricle in failing rat and human hearts

Abstract

SummaryThe molecular mechanisms of progressive right heart failure are incompletely understood. We systematically compared rat models of pulmonary artery or aortic banding to identify the transcriptomic changes that occur over months in the failing right versus left ventricle. Detailed bioinformatics analyses of 181 RNAseq datasets from cardiomyocytes or whole heart samples from these models, led to the identification of gene signatures, protein, and transcription factor networks specific to ventricles, compensated or decompensated disease states and type of heart failure. RNA-FISH approaches confirmed PAB-mediated regulation of key genes and revealed striking, spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with 95 transcriptome data sets from human patients with chronic thromboembolic pulmonary hypertension led to the identification of more than 50 genes whose expression levels strongly correlated with the severity of right heart disease. Together, these data define a conserved, differentially regulated genetic network that coordinates progressive right heart failure in rats and humans.HighlightsSide-by-side comparisons of RV or LV transcriptomes in the slowly failing rat heartIdentification of RV-specific gene sets in heart hypertrophy versus heart failureIdentification of RV gene sets correlating with severity of human CTEPHDevelopment of a core gene signature characteristic for RV failure