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

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.

Epigenetic mechanisms and potential therapeutic targets in stroke

“…93 The protein methyltransferase SET and MYND domain-containing protein 2 (SMYD2) histone methyltransferase that methylates H3K4 or H3K36 was shown to increase in the cortical peri-infarct region and SMYD2 knockout reduced BBB breakdown, edema, neurological deficits, and secondary brain damage following transient MCAO in mice. 94 In vitro analysis of primary rat brain microvascular endothelial cells showed that SMYD2 regulates the sphingosine kinases involved in endothelial cell barrier integrity via methylation-mediated ubiquitin-dependent degradation after OGD, indicating that SMYD2 potentiates post-ischemic BBB disruption. 94 In the astrocytes of middle-aged female mice, H3K4 histone methyltransferase activity was decreased compared to adult female mice following transient MCAO.…”

“…94 In vitro analysis of primary rat brain microvascular endothelial cells showed that SMYD2 regulates the sphingosine kinases involved in endothelial cell barrier integrity via methylation-mediated ubiquitin-dependent degradation after OGD, indicating that SMYD2 potentiates post-ischemic BBB disruption. 94 In the astrocytes of middle-aged female mice, H3K4 histone methyltransferase activity was decreased compared to adult female mice following transient MCAO. 30 Concomitantly, adult female mice displayed higher enrichment of H3K4me3 (transcriptional enhancer) versus H3K9me3 (transcriptional repressor) compared to middle-aged mice, indicating less active chromatin in the astrocytes of aged females after stroke.…”

Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm?

“…The other isoform, Sphk2, is necessary to regulate junctional protein expression and BBB protection in hypoxic preconditioning-induced cerebral ischemic tolerance in rats [ 213 ]. The histone methyltransferase Smyd2-dependent methylation of the Sphk/S1PR signaling pathway produces BBB disruption in experimental ischemic stroke in rats [ 214 ]. The preservation of S1P levels produced by the downregulation of SGPL1 enhances barrier function in human cerebral microvascular endothelial cells following an inflammatory challenge [ 178 ].…”

Protective effects of brain and muscle ARNT-like gene 1 on oxidized low-density lipoprotein-induced human brain microvascular endothelial cell injury by alleviating ferroptosis

“…Many studies have shown that oxidized low-density lipoprotein (ox-LDL)-associated brain microvascular endothelial cell injury is strongly related to the progression of atherosclerotic cerebrovascular diseases. 1,2 Therefore, elucidating the molecular mechanism of ox-LDL-induced brain microvascular endothelial cell injury is of great significance for alleviating cerebrovascular atherosclerosis.…”