Abstract
Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.
Highlights
The breakdown of the blood-brain barrier (BBB) and the infiltration of monocytes and neutrophils are critical steps toward severe inflammation of acute ischemic stroke [1, 2]
These results suggest that degradation of heparan sulfate (HS) and chondroitin sulfate (CS) in brain tissues occurs during hyperacute and acute phases after stroke onset
We discovered that HS in infarct lesion was degraded by HPSE after onset of stroke (Fig. 1)
Summary
The breakdown of the blood-brain barrier (BBB) and the infiltration of monocytes and neutrophils are critical steps toward severe inflammation of acute ischemic stroke [1, 2]. HS degradation and induction of proHPSE expression, via exposure to acrolein (ACR: CH2 = CH 2 CHO), a highly reactive unsaturated aldehyde produced during the stroke [14], were observed in immortalized human brain microvascular endothelial cells (HBMEC/cib) [15]. Glycocalyx dysfunction, due to HPSE or MMP9, in several diseases [10,11,12, 16] and increased levels of HYAL1 and 2 in infarct lesions of ischemic stroke patients were reported [17].
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