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Published on: March 30, 2019
Implication of MicroRNA503 in Brain Endothelial Cell Function and Ischemic Stroke
Huiting Zhang1, Qunwen Pan1, Zi Xie1
1Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, 57 South Renmin Road, Zhanjiang, 524001, China.
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.
Insights
Plasma miR-503 levels are elevated in ischemic stroke (IS) patients and correlate with disease severity. This microRNA plays a key role in brain endothelial cell function and may represent a novel therapeutic target for IS.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- The role of microRNA-503 (miR-503) in the brain endothelium and its involvement in ischemic stroke (IS) are not well understood.
- Investigating miR-503's relationship with IS onset, severity, subtypes, and associated biomarkers like von Willebrand Factor (vWF) is crucial.
Purpose of the Study:
- To examine the association between plasma miR-503 levels and clinical characteristics of IS patients.
- To elucidate the functional role and molecular mechanisms of miR-503 in cerebral endothelial cells using mouse models and in vitro studies.
Main Methods:
- Analysis of plasma miR-503 levels in IS patients, correlating with clinical data and vWF.
- Utilizing middle cerebral artery occlusion (MCAO) mouse models and cultured human cerebral vascular endothelial cells (ECs).
- Investigating the effects of miR-503 manipulation (overexpression/knockdown, antagomir treatment) on ECs' barrier function, apoptosis, ROS, and NO production, and analyzing key signaling pathways (PI3K/Akt/eNOS) and apoptosis markers (cleaved caspase-3, bcl-2).
Main Results:
- Plasma miR-503 levels were significantly elevated in IS patients, particularly in acute and severe cases, and correlated positively with vWF.
- miR-503 was identified as an independent risk factor for IS, with strong diagnostic potential (AUC=0.796).
- In MCAO mice and cultured ECs, miR-503 modulated endothelial barrier integrity, apoptosis, ROS, and NO production, primarily through the PI3K/Akt/eNOS pathway and apoptosis-related proteins.
Conclusions:
- miR-503 is a potential biomarker for ischemic stroke diagnosis and prognosis.
- miR-503 plays a significant role in the pathogenesis of ischemic stroke by affecting cerebral endothelial cell function.
- Targeting miR-503 presents a novel therapeutic strategy for ischemic stroke.
