RNA-Seq identifies novel myocardial gene expression signatures of heart failure

Heart failure comprises of clinically distinct inciting causes but a consistent pattern of change in myocardial gene expression supports the hypothesis that unifying biochemical mechanisms underlie disease progression. The recent RNA-seq revolution has enabled whole transcriptome profiling, using deep-sequencing technologies. Up to 70% of the genome is now known to be transcribed into RNA, a significant proportion of which is long non-coding RNAs (lncRNAs), defined as polyribonucleotides of ≥200 nucleotides. This project aims to discover whether the myocardium expression of lncRNAs changes in the failing heart. Paired end RNA-seq from a 300-400bp library of ‘stretched’ mouse myocyte total RNA was carried out to generate 76-mer sequence reads. Mechanically stretching myocytes with equibiaxial stretch apparatus mimics pathological hypertrophy in the heart. Transcripts were assembled and aligned to reference genome mm9 (UCSC), abundance determined and differential expression of novel transcripts and alternative splice variants were compared with that of control (non-stretched) mouse myocytes. Five novel transcripts have been identified in our RNA-seq that are differentially expressed in stretched myocytes compared with non-stretched. These are regions of the genome that are currently unannotated and potentially are transcribed into non-coding RNAs. Roles of known lncRNAs include control of gene expression, either by direct interaction with complementary regions of the genome or association with chromatin remodelling complexes which act on the epigenome.Changes in expression of genes which contribute to the deterioration of the failing heart could be due to the actions of these novel lncRNAs, immediately suggesting a target for new pharmaceuticals. Changes in the expression of these novel transcripts will be validated in a larger sample size of stretched myocytes vs non-stretched myocytes as well as in the hearts of transverse aortic constriction (TAC) mice vs Sham (surgical procedure without the aortic banding). In vivo investigations will then be carried out, using siLNA antisense technology to silence novel lncRNAs in mice.

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The relationship between myocardial gene expression of inducible nitric oxide synthase (NOS2) and the degree of myocardial inflammation and dysfunction in patients with chronic heart failure

Journal of Cardiac Failure ◽

10.1016/s1071-9164(03)00463-9 ◽

2003 ◽

Vol 9 (5) ◽

pp. S34

Author(s):

Wai Hong W. Tang ◽

Fernando Lopez ◽

Yin-Gail Yee ◽

Annie Mullin ◽

Ying Zhang ◽

...

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Heart Failure ◽

Chronic Heart Failure ◽

Inducible Nitric Oxide Synthase ◽

Myocardial Inflammation ◽

Oxide Synthase ◽

Myocardial Gene Expression ◽

The Relationship ◽

Inducible Nitric Oxide

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Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1β in heart failure

Cardiovascular Research ◽

10.1093/cvr/cvz232 ◽

2019 ◽

Vol 116 (7) ◽

pp. 1311-1322 ◽

Cited By ~ 1

Author(s):

Kenneth Bilchick ◽

Hema Kothari ◽

Aditya Narayan ◽

James Garmey ◽

Abdullah Omar ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Cardiac Resynchronization Therapy ◽

Mononuclear Cells ◽

Interleukin 1Β ◽

Cardiac Resynchronization ◽

Rna Seq ◽

Resynchronization Therapy ◽

Peripheral Blood Mononuclear ◽

Baseline Serum

Abstract Aims In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1β (IL-1β) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure. Methods and results We used RNA sequencing (RNA-Seq) and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to identify gene expression changes in PBMCs in response to CRT. In total, 27 patients were analysed: 12 with heart failure undergoing CRT, 6 with heart failure undergoing standard implanted cardioverter defibrillators, and 9 with coronary artery disease but not heart failure. In CRT patients (median age 65.5 years, interquartile range 63.0–66.8 years, 33% female), RNA-Seq analysis identified 40 genes, including multiple genes associated with the IL-1β pathway, with significant correlations (false discovery rate < 0.05) with four key CRT response measures. CRT was associated with suppression of PBMC expression of IL-1β (1.80-fold decrease, P = 0.047), FOS proto-oncogene (FOS) (3.25-fold decrease, P = 0.01), dual specificity phosphatase 1 (DUSP1) (2.05-fold decrease, P = 0.001), and early growth response 1 (EGR1) (7.38-fold decrease, P = 0.03), and suppression was greater in responders vs. non-responders (P = 0.03 for IL-1β, P = 0.02 for FOS, P = 0.02 for DUSP1, and P = 0.11 for EGR1). Baseline FOS and DUSP-1 levels were greater in responders vs. non-responders (6.15-fold higher, FOS, P = 0.002; 2.60-fold higher, DUSP1, P = 0.0001). CRT responders but not non-responders showed higher baseline gene expression of FOS (P = 0.04) and DUSP1 (P = 0.06) compared with control patients without heart failure. Baseline serum high-sensitivity C-reactive protein levels were 3.47-fold higher in CRT responders vs. non-responders (P = 0.008). Conclusion Treatment of heart failure with CRT resulted in decreased PBMC expression of genes linked to inflammation. Moreover, CRT responders had higher expression of these inflammatory genes prior to CRT and greater suppression of these genes after CRT compared with non-responders.

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