The regulatory roles of circular RNAs via autophagy in ischemic stroke

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The regulatory roles of circular RNAs via autophagy in ischemic stroke

Xiaoqin Li^1†, Lingfei Li^2†, Xiaoli Si^3†, Zheng Zhang¹, Zhumei Ni⁴, Yongji Zhou², Keqin Liu², Wenqing Xia², Yuyao Zhang¹, Xin Gu¹, Jinyu Huang⁵, Congguo Yin^1,2*, Anwen Shao^6,7* and Lin Jiang^1,2*

• ¹The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
• ²Department of Neurology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
• ³Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
• ⁴Department of Emergency, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
• ⁵Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
• ⁶Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
• ⁷Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Disease, Hangzhou, China

Ischemic stroke (IS) is a severe disease with a high disability, recurrence, and mortality rates. Autophagy, a highly conserved process that degrades damaged or aging organelles and excess cellular components to maintain homeostasis, is activated during IS. It influences the blood–brain barrier integrity and regulates apoptosis. Circular RNAs (circRNAs) are novel non-coding RNAs involved in IS-induced autophagy and participate in various pathological processes following IS. In addition, they play a role in autophagy regulation. This review summarizes current evidence on the roles of autophagy and circRNA in IS and the potential mechanisms by which circRNAs regulate autophagy to influence IS injury. This review serves as a basis for the clinical application of circRNAs as novel biomarkers and therapeutic targets in the future.

Introduction

Stroke is a leading cause of death and disability worldwide (1) and can be classified as ischemic stroke (IS) or hemorrhagic stroke (2). The major type is IS, accounting for 71% of cases (2). During IS, ischemia and hypoxia cause neuronal and glial anoxic depolarization (3), which increases extracellular levels of glutamate, leading to excess calcium influx and release of calcium from intracellular stores (4). Increased intracellular calcium contributes to neuronal nitric oxide synthase activation with consequent free radical production and the initiation of cell death processes, including apoptosis, necrosis, necroptosis, and autophagy. Current effective treatments for IS include restoration of blood flow through intravenous thrombolysis and neuroscientific intravascular recanalization, both of which reduce disability (2); however, these treatment methods are still limited owing to the limited time window, numerous contraindications (5), and high risk of hemorrhagic complications (6).

Autophagy is activated to varying degrees after IS to restore neuronal homeostasis (2, 7). Autophagy functions in IS by sequestering damaged or aged organelles, superfluous proteins, and cellular components into double membrane-bound vesicles, delivering cytoplasmic cargo to the lysosome, to which it subsequently fuses to form an autolysosome, finally leading to digestion and recycling (8). Autophagy presents a dual effect following ischemic insult. Mild to moderate induction of autophagy can be protective in IS (9), whereas an excessive increase in autophagic activity might be harmful owing to the cytosolic accumulation of autophagosomes and enhanced degradation of essential cellular components (10). Autophagy is divided into two groups according to the role it plays in IS: maladaptive and adaptive autophagy (11).

Circular RNAs are a novel type of non-coding RNAs (12) with a stable and evolutionally conserved covalent loop structure (13). Previous studies have demonstrated that circRNAs are often specifically expressed in tissue and developmental stages (14) and are highly expressed in the mammalian brain (15). CircRNAs are upregulated during neuronal differentiation and are highly enriched in synapses (16). The role of circRNAs has been identified in several human diseases, including neurological disorders, cardiovascular diseases, diabetes mellitus, chronic inflammatory diseases, and cancer (17–21). Interestingly, circRNAs function in ischemic brain injury (22–25); therefore, they are potential biomarkers for IS and may serve as new therapeutic targets.

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