Mihály Ruppert1, Bence Ágg1, Krisztina Pálóczi2, Kálmán Benke1, István Hartyánszky1, Béla Merkely1, Tamás Radovits1
1 Heart and Vascular Center, Semmelweis University
2 Department of Genetics, Cell- and Immunobiology, Semmelweis University
Introduction: MicroRNAs (miRNA) are short, non-coding RNA sequences that regulate gene expression on the post-transcriptional level. Recently, alterations in miRNA expression have been suggested to contribute to the development of chronic heart failure (CHF).
Aims: In the present investigation we aimed to explore potential alterations in miRNA expression in human end-stage CHF. Furthermore, we investigated the regulatory effects of the altered miRNAs on gene expression.
Methods: Molecular measurements were performed on human myocardial samples from the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University. Accordingly, in the CHF group (n=12) samples were collected from end-stage CHF patients undergoing heart transplantation. As control samples (n=12), papillary muscles were collected from patients undergoing mitral valve replacement. Patients in the control group had preserved cardiac function and were matched in age, sex and comorbidities with the CHF group. Global miRNA expression profiling of myocardial samples from the CHF and the control groups was carried out using Nanostring technology. Bioinformatics analysis of differentially expressed miRNAs was performed to predict relevant miRNA-target interactions. Predicted genes were classified into distinct pathways and ordered according to the number of up- or downregulated interacting miRNAs. mRNA expression of the predicted target genes was measured by qPCR.
Results: 31 miRNAs were significantly differentially expressed in the CHF compared to the control group. Bioinformatics revealed 3619 possible miRNA-target interactions The insulin and insulin-like growth factor (IGF) pathway emerged as one of the most strongly regulated pathways. Three predicted genes of these specific pathways, namely IGF 1 receptor (IGFR1), RAC-alpha serine/threonine-protein kinase (AKT1) and cAMP responsive element binding protein 1 (CREB1) showed decreased mRNA expression in the CHF compared to the control group.
Conclusion: Our results indicate that miRNA expression is dysregulated in human CHF, and these alterations might contribute to the downregulation of the insulin/IGF factor pathway.
Doctoral School: Basic and Translational Medicine
Program: Cardiovascular Disorders: Physiology and Medicine of Ischaemic Circulatory Diseases
Supervisor: Tamás Radovits