Preview

PDF, German Download (7MB) | Terms of use

Abstract

Sudden cardiac death (SCD) is a common mode of death in heart failure (HF) and results from prolonged action potential duration (APD) and ventricular arrhythmias. During the pathogenesis and progression of HF, a myriad number of signaling pathways are altered, including microRNAs. microRNAs are small noncoding RNAs that fine-tune gene expression by translational repression or transcript destabilization. Interestingly, microRNAs are dysregulated during HF, suggesting a potential involvement in the development and progression of the disease. Here, miR-19 was identified as an important regulator of heart function. Zebrafish lacking miR-19 developed severe bradycardia and reduced cardiac contractility. While mammals express two isoforms of miR-19, the zebrafish genome encodes for four members (19a-d). The reduction of miR-19b specifically was found to be sufficient to reduce heart rate by 30 % and to induce heart failure. Patch-clamp experiments from whole hearts showed that miR-19b deficient zebrafish exhibit significantly prolonged ventricular APD caused by impaired repolarization. Additionally these fish show increased sensitivity to an AV-Block, which is a characteristic feature of long QT-Syndrome in zebrafish. qRT-PCR revealed that miR-19b directly and indirectly regulates the expression of cardiac ion channels and thereby modulates APD and shape. This study describes miR-19b as an essential regulator of electrical activity of the heart and identifies it as a potential candidate gene causative for human long QT syndrome.