Neuroprotective Effect of miR-483-5p Against Cardiac Arrest-Induced Mitochondrial Dysfunction Mediated Through the TNFSF8/AMPK/JNK Signaling Pathway

Abstract

Substantial morbidity and mortality are associated with postcardiac arrest brain injury (PCABI). MicroRNAs(miRNAs) are essential regulators of neuronal metabolism processes and have been shown to contribute to alleviated neurological injury after cardiac arrest. In this study, we identified miRNAs related to the prognosis of patients with neurological dysfunction after cardiopulmonary resuscitation based on data obtained from the Gene Expression Omnibus (GEO) database. Then, we explored the effects of miR-483-5p on mitochondrial biogenesis, mitochondrial-dependent apoptosis, and oxidative stress levels after ischemia‒reperfusion injury in vitro and in vivo. MiR-483-5p was downregulated in PC12 cells and hippocampal samples compared with that in normal group cells and hippocampi. Overexpression of miR-483-5p increased the viability of PC12 cells after ischemia‒reperfusion injury and reduced the proportion of dead cells. A western blot analysis showed that miR-483-5p increased the protein expression of PCG-1, NRF1, and TFAM and reduced the protein expression of Bax and cleaved caspase 3, inhibiting the release of cytochrome c from mitochondria and alleviating oxidative stress injury by inhibiting the production of ROS and reducing MDA activity. We confirmed that miR-483-5p targeted TNFSF8 to regulate the AMPK/JNK pathway, thereby playing a neuroprotective role after cardiopulmonary resuscitation. Hence, this study provides further insights into strategies for inhibiting neurological impairment after cardiopulmonary resuscitation and suggests a potential therapeutic target for PCABI.

Potential diagnostic biomarkers: 6 cuproptosis- and ferroptosis-related genes linking immune infiltration in acute myocardial infarction

“…MiR-4798-3p was indicated to modulate TLR4 and STAT3, and it was closely linked with the prevalence of atrial fibrillation in males and also could regulate genes involved in the pathogenesis of AF [63]. MiR-483-5p was found to be elevated in people with AF, which suggests that it could be used to predict AF [64], and it can exert neuroprotective effects after cardiopulmonary resuscitation by blocking ROS production and reducing MDA activity to attenuate oxidative stress injury [65]. Furthermore, studies have shown that miR-483-5p is associated with coronary plaque rupture and the formation of local thrombi, and its expression is significantly increased in both autoimmune myocarditis and acute myocardial infarction (AMI) [66,67].…”

Impacts of MicroRNA-483 on Human Diseases

“…According to recent studies, miR-483-5p plays a crucial role in protecting against neurological injury induced by cardiac arrest. Specifically, miR-483-5p is significantly downregulated in hippocampal samples from patients with neurological injury after cardiac arrest compared to the normal group [ 61 ] ( Table 1 , Figure 2 ). Brain injury following cardiac arrest is mainly caused by the generation of mitochondrial reactive oxygen species (ROS), which can be inhibited by promoting mitochondrial biogenesis and reducing ROS generation.…”

“…MiR-483-5p targets TNFSF8 to achieve this effect and protect against neurological impairment. Overexpression of miR-483-5p reduces protein expression of Bax and cleaved caspase 3, thereby inhibiting cytochrome c release and ROS generation from mitochondria, which alleviates cell injury by ischemia–reperfusion [ 61 ]. The inhibition of miR-483-5p in rats results in more severe hippocampal damage than the control group after cardiac arrest.…”