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Anesthetic propofol overdose causes vascular hyperpermeability by reducing endothelial glycocalyx and ATP production.

ABSTRACT: Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions.

SUBMITTER: Lin MC

PROVIDER: S-EPMC4490431 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Project description:Pathological hyperpermeability is a morbidity involved in various systemic diseases, including sepsis. The endothelial glycocalyx layer (GCX) plays a key role in controlling vascular permeability and could be a useful therapeutic target. The purpose of the present study was to analyze the functional role of the GCX in vascular permeability and to elucidate its role in pathological conditions. First, male C57BL/6J wild-type mice were used as in vivo models to study the effects of sepsis and the pharmacological digestion of glycosaminoglycans (GAGs) on the GCX. Vascular permeability was evaluated using fluorescein isothiocyanate (FITC)-labeled dextran. Second, the changes in gene expression in vascular endothelial cells after GAGs digestion were compared between a control and a septic model using RNA sequencing. In the in vivo study, the glycocalyx was depleted in both the septic model and the group with pharmacological GAGs digestion. FITC-labeled dextran had leaked into the interstitium in the septic group, but not in the other groups. In the in vitro study, histamine decreased the transendothelial electrical resistance (TEER), indicating an increase in permeability. GAGs digestion alone did not change the TEER, and the effect of histamine on the TEER was not enhanced by GAGs digestion. The gene expression profiles after GAGs digestion differed from the control condition, indicating the initiation of signal transduction. In conclusion, we demonstrated that the structural barrier of the GCX does not solely determine the fluid permeability of the endothelial layer, since enzymatic depletion of the GCX did not increase the permeability. The gene expression findings suggest that the digestion of GAGs alone did not induce hyperpermeability either in vitro or in vivo, although sepsis did induce hyperpermeability. While GAGs degradation by itself does not appear to induce hyperpermeability, it may play an important role in initiating signal transductions.

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Anesthetic propofol overdose causes vascular hyperpermeability by reducing endothelial glycocalyx and ATP production.

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