Transcriptional Effects of E3 Ligase Nrdp1 on Hypertrophy in Neonatal Rat Cardiomyocytes by Microarray and Integrated Gene Network Analysis

Abstract

Objective: Neuregulin receptor degradation protein-1 (Nrdp1) is a novel E3 ubiquitin ligase, and we have previously shown that overexpression of Nrdp1 increased cardiomyocyte injury. However, the role of Nrdp1 in myocardial hypertrophy is unclear. In the present study, we clarified the molecular mechanisms of angiotensin II (Ang II)-induced cardiomyocyte hypertrophy regulated by Nrdp1 based on genome-wide transcriptional analysis. Methods: Neonatal rat cardiomyocytes were infected with adenoviruses containing green fluorescent protein (Ad-GFP) or wild-type Nrdp1 (Ad-Nrdp1), and then treated with Ang II for 36 h. Detection of differentially expressed genes was achieved with an Affymetrix Rat Gene 2.0 Array and Cluster and Java TreeView software. Results and Conclusion: Microarray data analysis demonstrated that Nrdp1 overexpression affected the expression of 12,140 mRNA genes in Ang II-induced cardiomyocyte hypertrophy, including the upregulation of 12,044 and the downregulation of 96. Gene ontology and globe signal transduction network analysis showed that Nrdp1 affected the expression of many genes related to stimulus response, the cell receptor pathway, and cell growth. Pathway network analysis identified myocardial metabolism, DNA replication, and the cell cycle as the most important pathways targeted by Nrdp1. lncRNA-mRNA coexpression network analysis showed that two core lncRNAs, NONRATT057160 and NONRATT054243, were involved in cardiomyotrophy regulated by Nrdp1 in cardiomyocytes. Taken together, these data provide compelling clues for further exploration of the function of Nrdp1 in heart disease.