NOS1AP Destruction Enhanced Susceptibility to Oxidative Stress in Doxorubicin-Induced Cardiomyopathy

Introduction: GWAS found association of NOS1AP with QT interval variations and sudden cardiac death. We aimed to clarify the role of NOS1AP in acute oxidative stressed condition. Methods: NOS1AP knockout (KO) and wild-type (WT) mouse were injected doxorubicin (DOX; 25 mg/kg) or normal saline (NS). ECG and ultrasound echocardiogram (UCG) were recorded before and 5 days after injection. Subgroup of mice underwent telemetry recording. Western blotting and histological analysis were performed to evaluate the production of reactive oxygen species (ROS). Results: ECG showed slightly longer QT interval in KO than WT. UCG showed significantly reduced fractional shortening at baseline (KO/WT 33%/38%). After DOX administration, KO exhibited significantly higher mortality than WT (KO/WT 58%/5%). Telemetry recording showed no lethal arrhythmias after DOX injection in either group. DOX administration prolonged QT interval and diminished FS in both groups; they were significantly more prominent in KO. NS injection did not affect in both mice. Production of ROS and oxidized products assessed by nitrotyrosine, hydroxynonenal, and dihydroethidium was significantly greater in KO than WT. Conclusion: NOS1AP KO mice exhibited enhanced susceptibility to oxidative stress, resulting in greater impairment of cardiac function and higher mortality in DOX-induced cardiomyopathy.