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.
Highlights
Propofol (2,6-diisopropylphenol) is a widely-used intravenous anesthetic for short-term sedation and general anesthesia during surgery
To examine the effects of a propofol overdose in vascular injury, we used the animal model described in Paragraph 2 of the Animal Experiments subsection of the Experimental Section
It is well known that impaired endothelial glycocalyx destroys the vascular barrier function, which leads to protein extravasation and tissue edema and is central in the pathophysiology of ischemia/reperfusion (I/R) injury [21] and many diseases, for example sepsis [22], atherosclerosis [23] and diabetes [24]
Summary
Propofol (2,6-diisopropylphenol) is a widely-used intravenous anesthetic for short-term sedation and general anesthesia during surgery. We previously showed that a propofol overdose induces endothelial necrosis-like cell death and vascular barrier dysfunction [9]. Among the proteoglycans present in endothelial glycocalyx are syndecans, perlecan and glypicans. Proteoglycans are shed from the endothelial surface in response to reactive oxygen species (ROS) and inflammatory mediators [18]. Their diminutions are associated with a wide range of pathological consequences, for example capillary leak syndrome, edema, aggravated inflammation, platelet hyperaggregation and loss of vascular responsiveness [14]. Considering the vascular dysfunction induced by a propofol overdose [9], the impairment of glycocalyx by a propofol overdose via reducing endothelial energy production has been hypothesized. HS, proteoglycan core protein (syndecan-1, syndecan-4, perlecan and glypican-1) expression, ATP production and its connections with glycocalyx injury were examined
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