Abstract
Variants of the nitric oxide synthase 1 adaptor protein (NOS1AP) locus are strongly related to QT interval prolongation and sudden cardiac death (SCD) in human. Our aim was to study the action of NOS1AP in the NTS by knockdown of NOS1AP using lentiviral vector‐mediated shRNA (Lv‐NOS1AP‐shRNA). qPCR data showed NOS1AP mRNA levels were expressed in NTS 3‐fold higher than organs such as kidney and heart in SD rats. Microinjection of Lv‐NOS1AP‐shRNA in NTS caused significant reduction in NOS1AP expression in SD rats. NOS1AP knockdown in NTS did not alter blood pressure (BP), heart rate (HR) recorded by radiotelemetry. ECG analysis revealed heart rate variability (HRV) was significantly reduced (SDNN, 51.2±5.6 vs 5.0±1.3 ms, P< .001) and QTc interval was markedly prolonged (72.4±4 vs 105±11 ms, P< .05) in NOS1AP knockdown rats. To study the cellular mechanism underlying NOS1AP action, we studied the effect of NOS1AP knockdown on glutamate‐induced neurotoxicity in Cath‐a cells. Treatment of cells with Lv‐NOS1AP‐shRNA significantly reduced NOS1AP expression, and was associated with increased glutamate‐induced neurotoxicity, suggesting a protective effect of NOS1AP. In summary, all results indicate that NOS1AP dysfunction in NTS might play an important role in the pathogenesis of cardiac arrhythmia which, in part, could be due to increased sensitivity to glutamate induced neurotoxicity.Research Support: NDSU‐COBRE
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