Abstract
Circular RNAs (circRNAs) are highly enriched in the central nervous system and significantly involved in a range of brain-related physiological and pathological processes. Ischemic stroke is a complex disorder caused by multiple factors; however, whether brain-derived circRNAs participate in the complex regulatory networks involved in stroke pathogenesis remains unknown. Here, we successfully constructed a cerebral ischemia-injury model of middle cerebral artery occlusion (MCAO) in male Sprague-Dawley rats. Preliminary qualitative and quantitative analyses of poststroke cortical circRNAs were performed through deep sequencing, and RT-PCR and qRT-PCR were used for validation. Of the 24,858 circRNAs expressed in the rat cerebral cortex, 294 circRNAs were differentially expressed in the ipsilateral cerebral cortex between the MCAO and sham rat groups. Cluster, GO, and KEGG analyses showed enrichments of these circRNAs and their host genes in numerous biological processes and pathways closely related to stroke. We selected 106 of the 294 circRNAs and constructed a circRNA-miRNA-mRNA interaction network comprising 577 sponge miRNAs and 696 target mRNAs. In total, 15 key potential circRNAs were predicted to be involved in the posttranscriptional regulation of a series of downstream target genes, which are widely implicated in poststroke processes, such as oxidative stress, apoptosis, inflammatory response, and nerve regeneration, through the competing endogenous RNA mechanism. Thus, circRNAs appear to be involved in multilevel actions that regulate the vast network of multiple mechanisms and events that occur after a stroke. These results provide novel insights into the complex pathophysiological mechanisms of stroke.
Highlights
Ischemic stroke and its sequelae, characterized by high mortality and disability rates, present a global medical problem and public health challenge [1]
To systematically investigate the genes and signaling pathways activated in response to pathological changes of cerebral hypoxia-ischemia, we successfully constructed a rat middle cerebral artery occlusion (MCAO) model capable of simulating an early stroke
Triphenyl tetrazolium chloride (TTC) staining was performed on the whole brains, and obvious morphological changes were observed in the brain tissues from the MCAO group compared with the sham group
Summary
Ischemic stroke and its sequelae, characterized by high mortality and disability rates, present a global medical problem and public health challenge [1]. The initiating factor for ischemic stroke is tissue ischemia, caused by cerebrovascular blockage, and the resulting ischemic cascade [2, 3]. The ischemic cascade is a complex series of events influenced by multiple factors and molecules [4, 5]. Focal cerebral hypoperfusion may trigger a sequence of cellular bioenergetic failures, inducing excitotoxicity [6], oxidative stress [7], damage to microvasculature [8], disruption of bloodbrain barrier function [9], and postischemic inflammation [10], leading to apoptosis [11] and necrosis [6] of neurons, neuroglia, and endothelial cells. The ATP deficiency after stroke leads to mitochondrial damage and further combines with reperfusion injury to trigger oxidative stress in brain tissues. In turn, aggravates existing mitochondrial damage, leading to the initiation of apoptosis through the release of apoptosis-inducing proteins in the ischemic core region [11].
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