Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo
Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo
复制标题
DOI：
10.1016/j.taap.2012.08.013
复制
发表时间：
2012-12-01
影响因子：
3.8
通讯作者：
Lin, Chiou-Feng
中科院分区：
文献类型：
--
作者：
Lin, Ming-Chung;Chen, Chia-Ling;Lin, Chiou-Feng
异丙酚的过量和长期应用可能会导致脑、心脏、肾脏、骨骼肌和免疫细胞等多个器官和组织的细胞毒性，但其潜在机制尚不清楚，尤其是在血管内皮细胞。我们先前的研究表明，在过量异丙酚治疗过程中，吞噬细胞中糖原合成酶-3(GSK-3)的激活是促凋亡的。关于异丙酚的血管内给药，我们因此假设异丙酚过量也通过GSK-3诱导内皮细胞毒性。异丙酚过量(100 mU g/ml)抑制人动脉和微血管内皮细胞的生长。治疗后，大多数内皮细胞经历了caspase非依赖性的坏死样细胞死亡。溶酶体膜通透性(LMP)后组织蛋白酶D的激活决定了坏死样细胞的死亡。此外，异丙酚过量还可诱导caspase依赖的细胞凋亡，至少部分Caspase-3被激活，并作用于线粒体跨膜电位(MTP)丢失的下游；然而，内皮细胞的凋亡不需要溶酶体组织蛋白。值得注意的是，GSK-3的激活是异丙酚过量诱导线粒体损伤和细胞凋亡的关键，但不是坏死性细胞死亡的关键。BALB/c小鼠腹腔注射过量异丙酚可导致腹膜血管通透性增加。这些结果表明，异丙酚过量在体外对内皮细胞具有细胞毒性作用，包括组织蛋白酶D调节的坏死样细胞死亡和GSK-3调节的线粒体凋亡，以及异丙酚在体内对内皮屏障的功能障碍。(C)2012 Elsevier Inc.保留所有权利。
An overdose and a prolonged treatment of propofol may cause cellular cytotoxicity in multiple organs and tissues such as brain, heart, kidney, skeletal muscle, and immune cells; however, the underlying mechanism remains undocumented, particularly in vascular endothelial cells. Our previous studies showed that the activation of glycogen synthase kinase (GSK)-3 is pro-apoptotic in phagocytes during overdose of propofol treatment. Regarding the intravascular administration of propofol, we therefore hypothesized that propofol overdose also induces endothelial cytotoxicity via GSK-3. Propofol overdose (100 mu g/ml) inhibited growth in human arterial and microvascular endothelial cells. After treatment, most of the endothelial cells experienced caspase-independent necrosis-like cell death. The activation of cathepsin D following lysosomal membrane permeabilization (LMP) determined necrosis-like cell death. Furthermore, propofol overdose also induced caspase-dependent apoptosis, at least in part Caspase-3 was activated and acted downstream of mitochondrial transmembrane potential (MTP) loss; however, lysosomal cathepsins were not required for endothelial cell apoptosis. Notably, activation of GSK-3 was essential for propofol overdose-induced mitochondrial damage and apoptosis, but not necrosis-like cell death. Intraperitoneal administration of a propofol overdose in BALB/c mice caused an increase in peritoneal vascular permeability. These results demonstrate the cytotoxic effects of propofol overdose, including cathepsin D-regulated necrosis-like cell death and GSK-3-regulated mitochondrial apoptosis, on endothelial cells in vitro and the endothelial barrier dysfunction by propofol in vivo. (C) 2012 Elsevier Inc. All rights reserved.