Abstract

Background: Heart failure (HF) is a complex condition where the heart cannot pump enough blood to the body. HF onset is preceded by cardiac hypertrophy (CH), an adaptative response to the increased workload that is characterized by an increase in cardiomyocyte size. Cardiac stressors such as Norepinephrine (NE) activate a global transcriptional response, controlled by different signaling cascades of master transcription factors (TFs, e.g., NFAT, GATA4, MEF2). However, considering the global scale of this transcriptional reprogramming we hypothesized that additional TFs could be involved in this complex response. Methods: Using a systems biology approach, we build a human genome-scale transcriptional regulatory network (TRN) to identify novel TF involved in CH/HF. First, we selected different public articles and databases to consolidate a human TRN template that comprises TF-TF and TFgene interactions. Second, we analyze public human HF transcriptomic datasets (RNAseq) to obtain differentially expressed genes. By integrating HF global gene expression into the human TRN, we generate a model of HF-response TRN. Interestingly, the network contains several TF involved in CH/HF along with novel uncharacterized factors, selecting BCL6 and SREBF1 as putative new regulators. To study BCL6 and SREBF1 transcriptional response under a CH condition, we performed RT-qPCR in neonatal rat cardiomyocytes treated with NE (20 µM, 48 h). Results and conclusions: We observed an increase in BCL6 and SREBF1 mRNA levels, correlated with the overexpression of classical hypertrophy marker genes (ANP, BNP and β-MHC1), and HF-response TFs (ATF4, NFATc4 and XBP1sp). This is the first report showing a human TRN for HF, a model which contains interesting new TF activated during CH, such as BCL6 and SREBF1. Our next goal is to evaluate the effects of BCL6 knockdown on cardiomyocyte hypertrophic growth and mitochondrial fragmentation.