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

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.

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.

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.

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.