Neurobiology of disease · 2023
Circular RNA CircPDS5B impairs angiogenesis following ischemic stroke through its interaction with hnRNPL to inactivate VEGF-A.
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Jiang Zhongzhong, Jiang Yugang
Аннотация
BACKGROUND: Ischemic stroke (IS) is the primary cause of mortality and disability worldwide. Circular RNAs (circRNAs) have been proposed as crucial regulators in IS. This study focused on the role of circPDS5B in IS and its underlying mechanism.
METHOD: Transient middle cerebral artery occlusion (tMCAO) mice and glucose deprivation/reoxygenation (OGD/R)-exposed human brain microvascular endothelial cells (BMECs) were used as IS models. Expression levels of circPDS5B, heterogenous nuclear ribonucleoprotein L (hnRNPL), runt-related transcription factor-1 (Runx1), and Zinc finger protein 24 (ZNF24) were quantified by qRT-PCR. MTT, wound healing, transwell and tube formation assays were employed to evaluate the cell proliferation, migration, and angiogenesis, respectively. Moreover, RNA pull-down, and RIP assay were performed to investigate the interaction among circPDS5B, hnRNPL and vascular endothelial growth factor-A (VEGF-A).
RESULTS: circPDS5B was significantly up-regulated in IS patients and tMCAO mice. Deficiency of circPDS5B relieved brain infarction and neuronal injury of tMCAO mice. OGD/R-induced apoptosis, inhibition in viability, migration, and angiogenesis in BMECs were dramatically abrogated by circPDS5B knockdown. Mechanistically, circPDS5B stabilized Runx1 and ZNF24 via recruiting hnRNPL, thereby suppressing the transcription and expression of VEGFA. hnRNPL silencing strengthened circPDS5B knockdown-mediated beneficial effect on IS.
CONCLUSION: Altogether, our study showed that high expression of circPDS5B exacerbated IS through recruitment of hnRNPL to stabilize Runx1/ZNF24 and subsequently inactivate VEGFA. Our findings suggest circPDS5B may be a novel therapeutic target for IS.
METHOD: Transient middle cerebral artery occlusion (tMCAO) mice and glucose deprivation/reoxygenation (OGD/R)-exposed human brain microvascular endothelial cells (BMECs) were used as IS models. Expression levels of circPDS5B, heterogenous nuclear ribonucleoprotein L (hnRNPL), runt-related transcription factor-1 (Runx1), and Zinc finger protein 24 (ZNF24) were quantified by qRT-PCR. MTT, wound healing, transwell and tube formation assays were employed to evaluate the cell proliferation, migration, and angiogenesis, respectively. Moreover, RNA pull-down, and RIP assay were performed to investigate the interaction among circPDS5B, hnRNPL and vascular endothelial growth factor-A (VEGF-A).
RESULTS: circPDS5B was significantly up-regulated in IS patients and tMCAO mice. Deficiency of circPDS5B relieved brain infarction and neuronal injury of tMCAO mice. OGD/R-induced apoptosis, inhibition in viability, migration, and angiogenesis in BMECs were dramatically abrogated by circPDS5B knockdown. Mechanistically, circPDS5B stabilized Runx1 and ZNF24 via recruiting hnRNPL, thereby suppressing the transcription and expression of VEGFA. hnRNPL silencing strengthened circPDS5B knockdown-mediated beneficial effect on IS.
CONCLUSION: Altogether, our study showed that high expression of circPDS5B exacerbated IS through recruitment of hnRNPL to stabilize Runx1/ZNF24 and subsequently inactivate VEGFA. Our findings suggest circPDS5B may be a novel therapeutic target for IS.