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Implication of MicroRNA503 in Brain Endothelial Cell Function and Ischemic Stroke

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Abstract

The role of miR-503 in brain endothelium and ischemic stroke (IS) remains unclear. We aimed to study the relationship between plasma miR-503 and the onset time, severity, subtypes, and von Willebrand Factor (vWF) level in IS patients and to investigate the roles and underlying mechanisms of miR-503 in middle cerebral artery occlusion (MCAO) mice and cultured cerebral vascular endothelial cells (ECs). In MCAO mice, the effects of plasma from acute severe IS patients (ASS) with or without miR-503 antagomir on brain and ECs damage were determined. In cultured human ECs, the effects of miR-503 overexpression or knockdown on the monolayer permeability, apoptosis, ROS, and NO generation were investigated. For mechanism study, the PI3K/Akt/eNOS pathway, cleaved caspase-3, and bcl-2 were analyzed. Results showed that plasma miR-503 was significantly increased in IS patients, especially in acute period and severe cases and subtypes of LAA and TACI, and was positively correlated with vWF. Logistic analysis indicated that miR-503 was an independent risk factor for IS, with the area under curve of 0.796 in ROC analysis. In MCAO mice, ASS pretreatment aggravated neurological injury, BBB damage, brain edema, CBF reduction, and decreased NO production while increased apoptosis and ROS generation in brain ECs, which were partly abolished by miR-503 antagomir. In cultured ECs, miR-503 overexpression and knockdown confirmed its effects on regulating monolayer permeability, cell apoptosis, NO, and ROS generation via PI3K/Akt/eNOS pathway or bcl-2 and cleaved caspase-3 proteins. These together indicate that miR-503 is a promising biomarker and novel therapeutic target for IS.

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Acknowledgments

This study was supported by National Natural Science Foundation of China (NSFC, no. 81771161, 81870580, 81770500) and Sailing Project of Guangdong Province (4YF17007G) and Guangdong Medical Research Foundation (B2018048) and Hundred-Talent Program of Affiliated Hospital of Guangdong Medical University.

Funding

This study was supported by National Natural Science Foundation of China (NSFC, no. 81771161, 81870580, 81770500) and Sailing Project of Guangdong Province (4YF17007G) and Guangdong Medical Research Foundation (B2018048) and Hundred-Talent Program of Affiliated Hospital of Guangdong Medical University.

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To the study conception and design. Material preparation, data collection, and analysis were performed by Huiting Zhang and Xiaotang Ma. Animal model was performed by Qunwen Pan. Human study was designed and launched by Bin Zhao and Huiting Zhang. The first draft of the manuscript was written by Xiaotang Ma and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bin Zhao or Xiaotang Ma.

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All procedures in studies involving human were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. And was approved and under supervision of ethics committee of affiliated Hospital of Guangdong Medical University (Human Investigation Committee PJ2016120). All procedures involving animals were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University (Permit Number: GDY1902025).

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Zhang, H., Pan, Q., Xie, Z. et al. Implication of MicroRNA503 in Brain Endothelial Cell Function and Ischemic Stroke. Transl. Stroke Res. 11, 1148–1164 (2020). https://doi.org/10.1007/s12975-020-00794-0

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