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Inducible over-expression of cardiac Nos1ap causes short QT syndrome in transgenic mice

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Item Type:Article
Title:Inducible over-expression of cardiac Nos1ap causes short QT syndrome in transgenic mice
Creators Name:Jansch, M. and Lubomirov, L.T. and Trum, M. and Williams, T. and Schmitt, J. and Schuh, K. and Qadri, F. and Maier, L.S. and Bader, M. and Ritter, O.
Abstract:Recent evidence demonstrated that alterations in the QT interval duration on the ECG are not only determined by mutations in genes for ion channels, but also by modulators of ion channels. Changes in the QT interval duration beyond certain thresholds are pathological and can lead to sudden cardiac death. We here focus on the ion channel modulator nitric oxide synthase 1 adaptor protein (Nos1ap). Whole-cell patch-clamp measurements of a conditional transgenic mouse model exhibiting cardiac specific Nos1ap over-expression revealed a Nos1ap-dependent increase of L-type calcium channel nitrosylation, which led to increased susceptibility to ventricular tachycardias associated with a decrease in QT duration and shortening of APD(90) duration. Survival was significantly reduced (60% after 12 weeks vs. 100% in controls). Examination of the structural features of the hearts of transgenic mice revealed constant heart dimensions and wall thickness without abnormal fibrosis content or BNP production after three months of Nos1ap over-expression compared to controls. Nos1ap over-expression did not alter cGMP production or ROS concentration. Our study showed that myocardial over-expression of Nos1ap leads to shortening of the QT interval and reduces survival rate of the transgenic animals, perhaps via development of ventricular arrhythmias. We conclude that Nos1ap overexpression causes targeted subcellular localization of Nos1 to the CaV1.2 with a subsequent decrease of ADP(90) and the QT interval. This causes detrimental cardiac arrhythmias in the transgenic mice.
Keywords:QT Interval Duration, L-Type Calcium Channel, NOS1AP, APD90, Animals, Mice
Source:FEBS Open Bio
Page Range:118-132
Date:January 2023
Official Publication:https://doi.org/10.1002/2211-5463.13520
PubMed:View item in PubMed

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