Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure. Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in heart failure remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts.
In this study, a team led by Harvard Medical School scientists performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n=15) and controls (n=15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in heart failure were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, they found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. The scientists overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of extracellular matrix synthesis genes. Moreover, they show that lncRNAs participate in the TGF- β pathway to modulate the expression of ECM genes and myofibroblast differentiation.
An enlarged image of association matrix of 145 differential expressed lncRNAs and 30 functional gene sets
based on Gene Set Enrichment Analysis (GSEA). Positive (red) and negative (blue) expression correlations are shown. Three clusters with positive expression correlation are boxed and labeled as a, b and c.
These studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ischemic cardiomyopathy. The results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ischemic cardiomyopathy.