MicroRNA-126-3p/-5p Overexpression Attenuates Blood-Brain Barrier Disruption in a Mouse Model of Middle Cerebral Artery Occlusion.

Abstract

Background and Purpose- Blood-brain barrier (BBB) disruption is a critical pathological feature after stroke. MicroRNA-126 (miR-126) maintains BBB integrity by regulating endothelial cell function during development. However, the role of miR-126-3p and -5p in BBB integrity after stroke is unclear. Here, we investigated whether miR-126-3p and -5p overexpression regulates BBB integrity after cerebral ischemia. Methods- A lentivirus carrying genes encoding miR-126-3p or -5p was stereotactically injected into adult male Institute of Cancer Research mouse brains (n=36). Permanent middle cerebral artery occlusion was performed 2 weeks after virus injection. Brain infarct volume, edema volume, and modified neurological severity score were assessed at 1 and 3 days after ischemia. Immunostaining of ZO-1 (zonula occludens-1) and occludin was used to evaluate BBB integrity. IL-1β (interleukin-1β), TNF-α (tumor necrosis factor-α), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin expression levels were determined by real-time polymerase chain reaction and Western blot analysis. Results- The expression of miR-126-3p and -5p decreased at 1 and 3 days after ischemia (P<0.05). Injection of lentiviral miR-126-3p or -5p reduced brain infarct volume and edema volume (P<0.05) and attenuated the decrease in ZO-1/occludin protein levels and IgG leakage at 3 days after stroke (P<0.05). Injection of lentiviral miR-126-5p improved behavioral outcomes at 3 days after stroke (P<0.05). miR-126-3p and -5p overexpression downregulated the expression of proinflammatory cytokines IL-1β and TNF-α and adhesion molecules VCAM-1 and E-selectin, as well as decreased MPO+ (myeloperoxidase positive) cell numbers at 3 days after ischemia (P<0.05). Conclusions- miR-126-3p and -5p overexpression reduced the expression of proinflammatory cytokines and adhesion molecules, and attenuated BBB disruption after ischemic stroke, suggesting that miR-126-3p and -5p are new therapeutic targets in the acute stage of stroke.

• Authors: Jiaji Pan, Meijie Qu, Yongfang Li, Liping Wang, Linyuan Zhang, Yongting Wang, Yaohui Tang, Heng-Li Tian, Zhijun Zhang, Guo-Yuan Yang
• Journal: Stroke (Stroke) Vol. 51 Issue 2 Pg. 619-627 (02 2020) ISSN: 1524-4628 [Electronic] United States
• PMID: 31822249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN126 microRNA, mouse
• MicroRNAs
• Occludin

Topics

• Animals
• Blood-Brain Barrier (metabolism)
• Brain Ischemia (genetics, pathology)
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Infarction, Middle Cerebral Artery (genetics, pathology)
• Mice
• MicroRNAs (genetics)
• Occludin (metabolism)
• Stroke (genetics, physiopathology)