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miR-19b - ein essentieller Regulator der Länge und Form des ventrikulären Aktionspotentials im Zebrafisch

Benz, Alexander

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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.

Item Type: Dissertation
Supervisor: Hassel, Prof. Dr. David
Date of thesis defense: 3 June 2016
Date Deposited: 01 Jul 2016 07:54
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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