Heart failure modulates long noncoding RNA expression in human left ventricles

Abstract

Purpose: Recently, high-throughput studies identified tens of thousands of sites transcribed to produce transcripts with little protein-coding potential. The function of these transcripts remains largely obscure and their relevance to cardiovascular disease is mostly undefined. Many non-protein-coding transcripts belong to the group of Long non coding RNAs (LncRNAs), which are arbitrarily classified according to their length >200 nt. They control protein targeting to genomic loci epigenetic silencing and serve as scaffolds for multiple proteins. To date no data are available on LncRNAs expression in human heart failure (HF) Methods and results: We measured the expression of 83 diseases-related LncRNAs using the LncRNA Profiler qPCR Array (SBI) in 13 left ventricular biopsies derived from patients affected by post-ischemic heart failure undergoing to left ventricle restoration procedure and in 12 controls, with no cardiomyopathy in order to identify a «HF-LncRNAs signature». Since type 2 diabetes (T2D) is an independent and powerful risk factor for HF development and diabetic patients also display increased risk of adverse cardiovascular events and higher total mortality, the presence of a «T2D HF-LncRNAs signature» was also investigated. The «HF-LncRNA signature» was then validated in a larger cohort of HF pts and controls by qPCR using home-designed primers avoiding any overlapping with sense and AS transcripts. After validation, we observed that in HF pts 14 LncRNAs were significantly modulated compared to healthy controls. In T2D-HF patients, 4 LncRNAs (DGCR5, H19-AS, HOTAIR, and RMRP) were differentially modulated compared to non-T2D-HF patients. Transcriptomic alterations mediated by the up-or down-regulation of HF-modulated LncRNAs in murine cardiomyocytes were investigated by Affymetrix GeneChip Exon 1.0 ST Arrays. Differentially expressed genes were analyzed by using Ingenuity Pathway Analysis software (IPA) and DAVID Functional Annotation Tool to identify enriched biological functions and pathways relevant for heart physiology and pathology. Conclusions: These findings suggest a role of LncRNAs in heart failure pathogenetic mechanisms.