Abstract
Sudden cardiac death due to ventricular arrhythmias often caused by action potential duration (APD) prolongation is a common mode of death in heart failure (HF). microRNAs, noncoding RNAs that fine tune gene expression, are frequently dysregulated during HF, suggesting a potential involvement in the electrical remodeling process accompanying HF progression. Here, we identified miR-19b as an important regulator of heart function. Zebrafish lacking miR-19b developed severe bradycardia and reduced cardiac contractility. miR-19b deficient fish displayed increased sensitivity to AV-block, a characteristic feature of long QT syndrome in zebrafish. Patch clamp experiments from whole hearts showed that miR-19b deficient zebrafish exhibit significantly prolonged ventricular APD caused by impaired repolarization. We found that miR-19b directly and indirectly regulates the expression of crucial modulatory subunits of cardiac ion channels, and thereby modulates AP duration and shape. Interestingly, miR-19b knockdown mediated APD prolongation can rescue a genetically induced short QT phenotype. Thus, miR-19b might represent a crucial modifier of the cardiac electrical activity, and our work establishes miR-19b as a potential candidate for human long QT syndrome.
Highlights
A frequent feature of cardiomyocytes from failing hearts, independent of the cause, is the prolongation of the action potential (AP) regularly caused by alterations in the functional expression of cardiac potassium and sodium channels[1,2,3,4]
The AP duration (APD) is determined by the balance between inward depolarizing and outward repolarizing currents during the plateau phase (Phase 2), with potassium currents playing a prominent role, including IK1, IKs and IKr34
Decreased potassium currents result in impaired repolarization and thereby lead to prolonged APD
Summary
A frequent feature of cardiomyocytes from failing hearts, independent of the cause, is the prolongation of the action potential (AP) regularly caused by alterations in the functional expression of cardiac potassium and sodium channels[1,2,3,4]. First evidence of a potential involvement in the heart came from a study demonstrating that depletion of the miR-17~92 cluster resulted in ventricular septal defects during cardiac development[9]. Song et al demonstrated that miR-19a/b positively influence cardiomyocyte hypertrophy by directly targeting MuRF-1 and atrogin-1, while a recent study showed that overexpression of miR-19a/b caused arrhythmia and bradycardia in zebrafish[12,13]. By patch-clamp we show that the action potentials recorded from miR-19b deficient zebrafish hearts are significantly prolonged. We further provide evidences that miR-19b modulates AP duration (APD), in part, by directly targeting KCNE4
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