Anesthetic Propofol Overdose Causes Vascular Hyperpermeability by Reducing Endothelial Glycocalyx and ATP Production
Anesthetic Propofol Overdose Causes Vascular Hyperpermeability by Reducing Endothelial Glycocalyx and ATP Production
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DOI：
10.3390/ijms160612092
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发表时间：
2015-06-01
影响因子：
5.6
通讯作者：
Hsing, Chung-Hsi
中科院分区：
文献类型：
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作者：
Lin, Ming-Chung;Lin, Chiou-Feng;Hsing, Chung-Hsi
大剂量丙泊酚长期给药可能引起弥漫性细胞毒性;然而，详细的潜在机制仍不清楚，特别是在血管内皮细胞中。以往的研究表明，异丙酚过量可诱导内皮损伤和血管屏障功能障碍。关于内皮糖萼在维持血管屏障完整性方面的重要作用，我们因此假设丙泊酚过量诱导的内皮屏障功能障碍是由受损的内皮糖萼引起的。在体内，我们腹腔注射过量丙泊酚，结果显示过量丙泊酚可显著诱导全身血管通透性增高，并降低多器官血管内皮糖萼、syndecan-1、syndecan-4、串珠素mRNA和硫酸乙酰肝素（HS）的表达。在体外，丙泊酚过量减少syndecan-1，syndecan-4，perlecan，磷脂酰肌醇蛋白聚糖-1 mRNA和HS的表达，并诱导显着降低烟酰胺腺嘌呤二核苷酸（NAD+）/NADH比值和ATP浓度在人微血管内皮细胞（HMEC-1）。寡霉素处理还诱导HMEC-1细胞中NAD+/NADH比率、ATP浓度以及多配体蛋白聚糖-4、串珠蛋白聚糖和磷脂酰肌醇蛋白聚糖-1 mRNA表达的显著降低。这些结果表明，异丙酚过量可诱导内皮糖萼表达部分ATP依赖性减少，从而因内皮屏障功能丧失而导致血管通透性过高。
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.