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H2S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells.
Toxicol Appl Pharmacol. 2018 01 01; 338:20-29.TA

Abstract

Hydrogen sulfide (H2S) is a novel gasotransmitter and acts as a multifunctional regulator in various cellular functions. Past studies have demonstrated a significant role of H2S and its generating enzyme cystathionine gamma-lyase (CSE) in the cardiovascular system. Lipopolysaccharide (LPS), a major pathogenic factor, is known to initiate the inflammatory immune response. The cross talk between LPS-induced inflammation and the CSE/H2S system in vascular cells has not yet been elucidated in detail. Here we showed that LPS decreased CSE mRNA and protein expression in human endothelial cells and blocked H2S production in mouse aorta tissues. Transfection of the cells with TLR4-specific siRNA knockdown TLR4 mRNA expression and abolished the inhibitory role of LPS on CSE expression. Higher dose of LPS (100μg/ml) decreased cell viability, which was reversed by exogenously applied H2S at physiologically relevant concentration (30μM). Lower dose of LPS (10μg/ml) had no effect on cell viability, but significantly induced inflammation gene expressions and cytokines secretion and stimulated cell hyper-permeability. H2S treatment prevented LPS-induced inflammation and hyper-permeability. Lower VE-cadherin expression in LPS-incubated cells would contribute to cell hyper-permeability, which was reversed by H2S co-incubation. In addition, H2S treatment blocked LPS-induced NFκB transactivation. We further validated that LPS-induced hyper-permeability was reversed by CSE overexpression but further deteriorated by CRISPR/Cas9-mediated knockout of CSE. In vivo, deficiency of CSE sensitized the mice to LPS-induced inflammation in vascular tissues. Take together, these data suggest that CSE/H2S system protects LPS-induced inflammation and cell hyper-permeability by blocking NFκB transactivation.

Authors+Show Affiliations

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Life Science, Shanxi University, Taiyuan, China.Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Human Kinetics, Laurentian University, Sudbury, Canada; Department of Biology, Laurentian University, Sudbury, Canada; Health Science North Research Institute, Sudbury, Canada.Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.School of Life Science, Shanxi University, Taiyuan, China.Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Human Kinetics, Laurentian University, Sudbury, Canada; Health Science North Research Institute, Sudbury, Canada.Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; Department of Biology, Laurentian University, Sudbury, Canada.Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada. Electronic address: gyang2@laurentian.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29128401

Citation

Bourque, Caitlyn, et al. "H2S Protects Lipopolysaccharide-induced Inflammation By Blocking NFκB Transactivation in Endothelial Cells." Toxicology and Applied Pharmacology, vol. 338, 2018, pp. 20-29.
Bourque C, Zhang Y, Fu M, et al. H2S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells. Toxicol Appl Pharmacol. 2018;338:20-29.
Bourque, C., Zhang, Y., Fu, M., Racine, M., Greasley, A., Pei, Y., Wu, L., Wang, R., & Yang, G. (2018). H2S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells. Toxicology and Applied Pharmacology, 338, 20-29. https://doi.org/10.1016/j.taap.2017.11.004
Bourque C, et al. H2S Protects Lipopolysaccharide-induced Inflammation By Blocking NFκB Transactivation in Endothelial Cells. Toxicol Appl Pharmacol. 2018 01 1;338:20-29. PubMed PMID: 29128401.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - H2S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells. AU - Bourque,Caitlyn, AU - Zhang,Yanjie, AU - Fu,Ming, AU - Racine,Mélanie, AU - Greasley,Adam, AU - Pei,Yanxi, AU - Wu,Lingyun, AU - Wang,Rui, AU - Yang,Guangdong, Y1 - 2017/11/08/ PY - 2017/07/10/received PY - 2017/10/23/revised PY - 2017/11/07/accepted PY - 2017/11/13/pubmed PY - 2018/1/13/medline PY - 2017/11/13/entrez KW - Cystathionine gamma-lyase KW - Endothelial cells KW - H(2)S KW - Inflammation KW - LPS KW - NFκB SP - 20 EP - 29 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 338 N2 - Hydrogen sulfide (H2S) is a novel gasotransmitter and acts as a multifunctional regulator in various cellular functions. Past studies have demonstrated a significant role of H2S and its generating enzyme cystathionine gamma-lyase (CSE) in the cardiovascular system. Lipopolysaccharide (LPS), a major pathogenic factor, is known to initiate the inflammatory immune response. The cross talk between LPS-induced inflammation and the CSE/H2S system in vascular cells has not yet been elucidated in detail. Here we showed that LPS decreased CSE mRNA and protein expression in human endothelial cells and blocked H2S production in mouse aorta tissues. Transfection of the cells with TLR4-specific siRNA knockdown TLR4 mRNA expression and abolished the inhibitory role of LPS on CSE expression. Higher dose of LPS (100μg/ml) decreased cell viability, which was reversed by exogenously applied H2S at physiologically relevant concentration (30μM). Lower dose of LPS (10μg/ml) had no effect on cell viability, but significantly induced inflammation gene expressions and cytokines secretion and stimulated cell hyper-permeability. H2S treatment prevented LPS-induced inflammation and hyper-permeability. Lower VE-cadherin expression in LPS-incubated cells would contribute to cell hyper-permeability, which was reversed by H2S co-incubation. In addition, H2S treatment blocked LPS-induced NFκB transactivation. We further validated that LPS-induced hyper-permeability was reversed by CSE overexpression but further deteriorated by CRISPR/Cas9-mediated knockout of CSE. In vivo, deficiency of CSE sensitized the mice to LPS-induced inflammation in vascular tissues. Take together, these data suggest that CSE/H2S system protects LPS-induced inflammation and cell hyper-permeability by blocking NFκB transactivation. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/29128401/H2S_protects_lipopolysaccharide_induced_inflammation_by_blocking_NFκB_transactivation_in_endothelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(17)30441-6 DB - PRIME DP - Unbound Medicine ER -