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

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 APD90 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 ADP90 and the QT interval. This causes detrimental cardiac arrhythmias in transgenic mice. We established and phenotyped a transgenic mouse model with cardiac‐specific over‐expression of nitric oxide synthase 1 adaptor protein (Nos1ap). We found increased nitrosylation of the L‐type calcium channel (CaV1.2) due to Nos1ap over‐expression, and patch‐clamp measurements showed a shortening of action potential duration. Nos1ap over‐expression resulted in a shortening of the QT interval on ECG, ventricular tachycardias and decreased survival rate without evidence of structural cardiac diseases.