M6A modification promotes blood-brain barrier breakdown during cerebral ischemia/reperfusion injury through increasing matrix metalloproteinase 3 expression

En Liang; Shaorong Xiao; Changtong Zhao; Yu Zhang; Guanglei Fu

doi:10.1016/j.heliyon.2023.e16905

M6A modification promotes blood-brain barrier breakdown during cerebral ischemia/reperfusion injury through increasing matrix metalloproteinase 3 expression

Heliyon. 2023 Jun 1;9(6):e16905. doi: 10.1016/j.heliyon.2023.e16905. eCollection 2023 Jun.

Authors

En Liang¹, Shaorong Xiao², Changtong Zhao¹, Yu Zhang³, Guanglei Fu⁴

Affiliations

¹ Department of Neurosurgery, Guangzhou PanYu He Xian Memorial Hospital, Guangzhou, 511442, PR China.
² Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China.
³ Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518133, PR China.
⁴ Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, PR China.

Abstract

Blood-brain barrier (BBB) breakdown is a critical event in cerebral ischemia-reperfusion (I/R) injury, and matrix metalloproteinases (MMPs), which are proteolytic enzymes, play essential roles in BBB breakdown through degrading the extracellular matrix. N6-Methyladenosine (m6A), the most common and reversible mRNA modification, has an important role in the progression of cerebral I/R injury. However, whether m6A is related to BBB breakdown and MMPs expression in cerebral I/R injury is still not clear. In this study, we explored the potential effects of m6A modification on BBB breakdown in cerebral I/R injury and its underlying mechanisms using mice subjected to transient middle cerebral artery occlusion and reperfusion (MCAO/R), and mouse brain endothelial cells treated with oxygen-glucose deprivation and reoxygenation (OGD/R). We find that MMP3 expression is highly expressed and positively associated with the m6A writer CBLL1 (Cbl proto-oncogene like 1) in cerebral I/R injury in vivo and in vitro. Furthermore, MMP3 mRNA occurs m6A modification in mouse brain endothelial cells, and the m6A modification level of MMP3 mRNA is significantly increased in cerebral I/R injury. Moreover, inhibition of m6A modification reduces MMP3 expression and ameliorates BBB breakdown in cerebral I/R in vivo and in vitro. In conclusion, m6A modification promotes BBB breakdown in cerebral I/R injury through increasing MMP3 expression, indicating that m6A may be a potential therapeutic target for cerebral I/R injury.

Keywords: Blood-brain barrier; Cerebral ischemia-reperfusion injury; Matrix metalloproteinase 3; N6-methyladenosine; Oxygen-glucose deprivation and reoxygenation.