Histone methyltransferase Smyd2 contributes to blood‐brain barrier breakdown in stroke

Abstract

Abstract Background The blood‐brain barrier (BBB) plays a principal role in the healthy and diseased central nervous systems, and BBB disruption after ischaemic stroke is responsible for increased mortality. Smyd2, a member of the SMYD‐methyltransferase family, plays a vital role in disease by methylation of diverse substrates; however, little is known about its role in the pathophysiology of the brain in response to ischaemia‐reperfusion injury. Methods Using oxygen glucose deprivation and reoxygenation (OGD/R)‐induced primary brain microvascular endothelial cells (BMECs) and Smyd2 knockdown mice subjected to middle cerebral artery occlusion, we evaluated the role of Smyd2 in BBB disruption. We performed loss‐of‐function and gain‐of‐function studies to investigate the biological function of Smyd2 in ischaemic stroke. Results We found that Smyd2 was a critical factor for regulating brain endothelial barrier integrity in ischaemia‐reperfusion injury. Smyd2 is upregulated in peri‐ischaemic brains, leading to BBB disruption via methylation‐mediated Sphk/S1PR. Knockdown of Smyd2 in mice reduces BBB permeability and improves functional recovery. Using OGD/R‐induced BMECs, we demonstrated that Sphk/S1PR methylation modification by Smyd2 affects ubiquitin‐dependent degradation and protein stability, which may disrupt endothelial integrity. Moreover, overexpression of Smyd2 can damage endothelial integrity through Sphk/S1PR signalling. Conclusions Overall, these results reveal a novel role for Smyd2 in BBB disruption in ischaemic stroke, suggesting that Smyd2 may represent a new therapeutic target for ischaemic stroke.

Keywords

• blood‐brain barrier
• brain microvascular endothelial cells
• ischaemia stroke
• Smyd2