Jaensch, Monique and Lubomirov, Lubomir T. and Trum, Maximilian and Williams, Tatjana and Schmitt, Joachim and Schuh, Kai and Qadri, Fatimunnisa and Maier, Lars S. and Bader, Michael and Ritter, Oliver (2023) Inducible over-expression of cardiac Nos1ap causes short QT syndrome in transgenic mice. FEBS OPEN BIO, 13 (1). pp. 118-132. ISSN 2211-5463,
Full text not available from this repository. (Request a copy)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 3 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 the shortening of the QT interval and reduces the survival rate of transgenic animals, perhaps via the 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 transgenic mice.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NITRIC-OXIDE SYNTHASE; 1 ADAPTER PROTEIN; DEATH; OVEREXPRESSION; PROLONGATION; ARRHYTHMIA; RISK; GENE; APD90; L-type calcium channel; NOS1AP; QT interval duration |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Mar 2024 11:25 |
| Last Modified: | 05 Mar 2024 11:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58503 |
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