SNTA1 inhibits the PI3K/AKT signaling pathway leading to increased mitochondrial dysfunction and arrhythmia caused by diacetylmorphine

Diacetylmorphine (DA) abuse can result in severe arrhythmias and even sudden death. Although previous research has connected ion channel proteins to arrhythmia occurrences, the precise mechanism underlying DA-induced arrhythmias remains poorly understood. This study conducted a comprehensive analysis of the myocardial toxicity of DA by applying proteomic and histopathological approaches and investigated the underlying mechanisms using in vitro experiments. In vivo experiments confirmed that DA induces cardiac arrhythmias, as evidenced by electrocardiographic analyses of rats. Additionally, Masson staining, wheat germ agglutinin staining (WGA) staining, and western blotting of myocardial tissues revealed significant myocardial damage. Tandem mass tag proteomics analysis identified syntrophin alpha 1 (SNTA1) as a pivotal target molecule linked to myocardial toxicity. Ex vivo experiments showed specific upregulation of SNTA1 in rat cardiomyocytes following DA exposure. Furthermore, in vitro experiments indicated that DA caused disruption of potassium channels and activated the arrhythmia-related PI3K/AKT signaling pathway. Silencing and overexpression studies of SNTA1 highlighted its role in ion channel abnormalities and that of the PI3K/AKT signaling pathway expression in cardiomyocytes, underscoring the crucial role of mitochondrial function in cardiac arrhythmias. This research indicates that SNTA1 is integral to arrhythmia development by influencing the PI3K/AKT signaling pathway, leading to mitochondrial dysfunction and ion channel irregularities. SNTA1 is a potential therapeutic target for DA-induced arrhythmias. This study enhances our understanding of DA-induced myocardial toxicity and offers valuable insights for assessing the risks of DA exposure in humans.