Abstract
Many hospitals lack facilities for accurate diagnosis of acute ischemic stroke (AIS). Circular RNA (circRNA) is highly expressed in the brain and is closely associated with stroke. In this study, we examined whether the blood-borne circRNAs could be promising candidates as adjunctive diagnostic biomarkers and their pathophysiological roles after stroke. We profiled the blood circRNA expression in mice subjected to experimental focal cerebral ischemia and validated the selected circRNAs in AIS patients. We demonstrated that 128, 198, and 789 circRNAs were significantly altered at 5 min, 3 h, and 24 h after ischemic stroke, respectively. Our bioinformatics analysis revealed that the circRNA-targeted genes were associated with the Hippo signaling pathway, extracellular matrix-receptor interaction, and fatty acid metabolism at 5 min, 3 h and 24 h after ischemic stroke, respectively. We verified that many of these circRNAs existed in the mouse brain. Furthermore, we found that most of the predicted circRNA-miRNA interactions apparently exhibited functional roles in terms of regulation of their target gene expression in the brain. We also verified that many of these mouse circRNAs were conserved in human. Finally, we found that circBBS2 and circPHKA2 were differentially expressed in the blood of AIS patients. These results demonstrate that blood circRNAs may serve as potential biomarkers for AIS diagnosis and reveal the pathophysiological responses in the brain after ischemic stroke.
Highlights
Stroke is the second most common cause of death worldwide, and many stroke survivors suffer from long-term disability, severely affecting the well-being of the patients and family members (GBD 2015 Mortality and Causes of Death Collaborators, 2016; Bazan et al, 2017)
Occlusion of blood flow of all animals was confirmed by blood perfusion imaging (Figure 1B). 2,3,5-triphenyl-tetrazolim chloride (TTC) staining was used to verify that middle cerebral artery occlusion (MCAO) for 5 min had not caused detectable brain damage whereas, at 3 h, MCAO had already initiated signs of brain infarction, as shown by the pale pink staining
The PHKA2 gene expresses the alpha subunit of phosphorylase b kinase (PBK) (Brushia and Walsh, 1999). This kinase is found in various tissues, with high expression in the liver and muscles (Mehta et al, 2017). It plays an important role in cellular energy metabolism, as PBK activates glycogen phosphorylase, which catabolizes glycogen when glucose is deprived (Brushia and Walsh, 1999)
Summary
Stroke is the second most common cause of death worldwide, and many stroke survivors suffer from long-term disability, severely affecting the well-being of the patients and family members (GBD 2015 Mortality and Causes of Death Collaborators, 2016; Bazan et al, 2017). The two major types of stroke are acute ischemic stroke (AIS), which occurs when blood flow through the artery that brings oxygen-rich blood to the brain is obstructed (usually due to a blood clot), and hemorrhagic stroke, which occurs when an artery in the brain ruptures (CDC, 2014). Because ischemic stroke is more common than hemorrhagic stroke (87% of cases), most stroke prevention investigations are focused on AIS (Meschia et al, 2014). The current standard treatment for stroke involves the administration of tissue plasminogen activator (t-PA) (Collen and Lijnen, 2009). A more accessible, non-invasive diagnostic method, such as a bloodbased biomarker, would be of great value for the diagnosis of AIS, swiftly assisting clinicians in choosing the most effective treatment strategy for stroke patients and leading to better outcomes
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