title: Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo.
abstract: 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 μg/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.
authors: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Ming-Chung
authors: MC
authors: Lin
authors: Chia-Ling
authors: CL
authors: Chen
authors: Tsan-Tzu
authors: TT
authors: Yang
authors: Pui-Ching
authors: PC
authors: Choi
authors: Chung-Hsi
authors: CH
authors: Hsing
authors: Chiou-Feng
authors: CF
authors: Lin
mesh_terms: D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015742:Propofol / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D018686:Anesthetics, Intravenous; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D002402:Cathepsin D; D015742:Propofol