Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy.

AIMS: Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy. METHOD AND RESULTS: Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity. CONCLUSION: H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

Non-coding RNA and Cardiac Electrophysiological Disorders.

Cardiac arrhythmias are common diseases affecting millions of people worldwide. A broad and diverse array of arrhythmias exists, ranging from harmless ones such as sinus arrhythmia to fatal disorders such as ventricular fibrillation. The underlying pathophysiology of arrhythmogenesis is complex and still not fully understood. Since their discovery, non-coding RNAs (ncRNAs) and especially microRNAs (miRNAs) came into the spotlight of arrhythmia research as it has been shown that they play an important role in regulating normal development of the cardiac conduction system and are involved in remodeling processes leading to arrhythmias. This chapter will give a brief overview on basic electrophysiologic concepts and will summarize the current knowledge on ncRNAs and their role in arrhythmogenesis.

MicroRNA 628-5p as a Novel Biomarker for Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the leading cause of morbidity and mortality after orthotopic heart transplantation (OHT). Because of its clinically silent progression and lack of symptoms, detection is often difficult and invasive coronary angiography is performed routinely. To date, there are no established noninvasive biomarkers available for prediction of CAV in transplanted patients.MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules that negatively regulate gene expression. As they are detectable in peripheral blood, recent studies have suggested miRNAs as biomarkers for various cardiovascular diseases. Thus, we hypothesized that circulating miRNAs may serve as noninvasive biomarkers for CAV. METHODS: To determine the regulation of circulating miRNAs, we performed miRNA profiling studies in plasma samples of OHT patients with confirmed high-degree CAV and a matched control group consisting of patients without any signs of CAV at least 5 years after OHT. Candidate miRNAs were verified by quantitative reverse transcriptase polymerase chain reaction. RESULTS: Microarray analysis revealed 5 candidate miRNAs (miR-34a, miR-98, miR-155, miR-204, miR-628-5p) that were differentially regulated in plasma samples of patients with CAV and therefore were selected for verification by quantitative reverse transcriptase polymerase chain reaction. In CAV patients, plasma levels of miR-628-5p and miR-155 were significantly increased (P = 0.001 and P = 0.028, respectively). A miR628-5p value above 1.336 was able to predict CAV with a sensitivity of 72% and a specificity of 83%. CONCLUSIONS: For the first time, the present study identifies the circulating miRNA miR-628-5p as a novel potential biomarker of CAV in patients after OHT.