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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-regulatedmore » mitochondrial apoptosis, on endothelial cells in vitro and the endothelial barrier dysfunction by propofol in vivo. Highlights: ► Propofol overdose causes apoptosis and necrosis in endothelial cells. ► Propofol overdose triggers lysosomal dysfunction independent of autophagy. ► Glycogen synthase kinase-3 facilitates propofol overdose-induced apoptosis. ► Propofol overdose causes an increase in peritoneal vascular permeability.« less

Authors:
 [1];  [2]; ;  [1];  [3];  [1]
  1. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan (China)
  2. Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan (China)
  3. Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan (China)
Publication Date:
OSTI Identifier:
22215995
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 265; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANESTHETICS; ANIMAL TISSUES; APOPTOSIS; BRAIN; CATHEPSINS; DIFFUSION BARRIERS; GLYCOGEN; HEART; IN VITRO; IN VIVO; KIDNEYS; MICE; MITOCHONDRIA; NECROSIS; PHAGOCYTES; TOXICITY

Citation Formats

Lin, Ming-Chung, Department of Anesthesiology, Chi Mei Medical Center, Liouying, Tainan, Taiwan, Chen, Chia-Ling, Yang, Tsan-Tzu, Choi, Pui-Ching, Hsing, Chung-Hsi, Department of Anesthesiology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Lin, Chiou-Feng, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.08.013.
Lin, Ming-Chung, Department of Anesthesiology, Chi Mei Medical Center, Liouying, Tainan, Taiwan, Chen, Chia-Ling, Yang, Tsan-Tzu, Choi, Pui-Ching, Hsing, Chung-Hsi, Department of Anesthesiology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Lin, Chiou-Feng, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, & Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo. United States. https://doi.org/10.1016/J.TAAP.2012.08.013
Lin, Ming-Chung, Department of Anesthesiology, Chi Mei Medical Center, Liouying, Tainan, Taiwan, Chen, Chia-Ling, Yang, Tsan-Tzu, Choi, Pui-Ching, Hsing, Chung-Hsi, Department of Anesthesiology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Lin, Chiou-Feng, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 2012. "Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo". United States. https://doi.org/10.1016/J.TAAP.2012.08.013.
@article{osti_22215995,
title = {Anesthetic propofol overdose causes endothelial cytotoxicity in vitro and endothelial barrier dysfunction in vivo},
author = {Lin, Ming-Chung and Department of Anesthesiology, Chi Mei Medical Center, Liouying, Tainan, Taiwan and Chen, Chia-Ling and Yang, Tsan-Tzu and Choi, Pui-Ching and Hsing, Chung-Hsi and Department of Anesthesiology, College of Medicine, Taipei Medical University, Taipei, Taiwan and Lin, Chiou-Feng and Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan and Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan},
abstractNote = {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. Highlights: ► Propofol overdose causes apoptosis and necrosis in endothelial cells. ► Propofol overdose triggers lysosomal dysfunction independent of autophagy. ► Glycogen synthase kinase-3 facilitates propofol overdose-induced apoptosis. ► Propofol overdose causes an increase in peritoneal vascular permeability.},
doi = {10.1016/J.TAAP.2012.08.013},
url = {https://www.osti.gov/biblio/22215995}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 265,
place = {United States},
year = {Sat Dec 01 00:00:00 EST 2012},
month = {Sat Dec 01 00:00:00 EST 2012}
}