Low molecular weight fucoidan restores diabetic endothelial glycocalyx by targeting neuraminidase2: A new therapy target in glycocalyx shedding

Abstract

Background and PurposeDiabetic vascular complication is a leading cause of disability and mortality in diabetes patients. Low molecular weight fucoidan (LMWF) is a promising drug candidate for diabetic vascular complications. Glycocalyx injury predates the occurrence of diabetes vascular complications. Protecting glycocalyx from degradation relieves diabetic vascular complications. Therefore, LMWF has the potential to protect the diabetes endothelial glycocalyx from shedding.Experimental ApproachThe protective effect of LMWF on diabetic glycocalyx damage was investigated in db/db mice and Human Umbilical Vein Endothelial Cells (HUVEC) through transmission electron microscopy and WGA labeling. The effect of LMWF on glycocalyx degrading enzymes expression was investigated. Neuraminidase2 (NEU2) overexpression/knockdown was performed in HUVEC to verify the important role of NEU2 in glycocalyx homeostasis. Physiological and biochemical indexes were detected to verify the effect of LMWF on blood homeostasis. The interaction between NEU2 and LMWF was detected by Elisa and SPR.Key ResultsLMWF normalizes blood indexes including insulin, triglyceride, uric acid and reduces diabetes complications adverse events. LMWF alleviates diabetic endothelial glycocalyx damage in db/db mice kidney/aorta and high concentration glucose treated HUVEC. NEU2 is up‐regulated in db/db mice and HUVEC with high concentration glucose. Overexpression/knockdown NEU2 results in glycocalyx shedding in HUVEC. Down‐regulation and interaction of LMWF with NEU2 is a new therapy target in glycocalyx homeostasis. Further study found NEU2 was positively correlated with phosphorylated IR‐β.Conclusion and ImplicationsNEU2 is an effective target for glycocalyx homeostasis and LMWF is a promising drug to alleviate vascular complications in diabetes by protecting endothelial glycocalyx from damage.