title: Nitroglycerine-induced nitrate tolerance compromises propofol protection of the endothelial cells against TNF-α: the role of PKC-β2 and NADPH oxidase.
abstract: Continuous treatment with organic nitrates causes nitrate tolerance and endothelial dysfunction, which is involved with protein kinase C (PKC) signal pathway and NADPH oxidase activation. We determined whether chronic administration with nitroglycerine compromises the protective effects of propofol against tumor necrosis factor (TNF-) induced toxicity in endothelial cells by PKC- β2 dependent NADPH oxidase activation. Primary cultured human umbilical vein endothelial cells were either treated or untreated with TNF- α (40 ng/mL) alone or in the presence of the specific PKC- β2 inhibitor CGP53353 (1 μM)), nitroglycerine (10 μM), propofol (100 μM), propofol plus nitroglycerin, or CGP53353 plus nitroglycerine, respectively, for 24 hours. TNF-α increased the levels of superoxide, Nox (nitrate and nitrite), malondialdehyde, and nitrotyrosine production, accompanied by increased protein expression of p-PKC-β2, gP91phox, and endothelial cell apoptosis, whereas all these changes were further enhanced by nitroglycerine. CGP53353 and propofol, respectively, reduced TNF-α induced oxidative stress and cell toxicity. CGP53353 completely prevented TNF- α induced oxidative stress and cell toxicity in the presence or absence of nitroglycerine, while the protective effects of propofol were neutralized by nitroglycerine. It is concluded that nitroglycerine comprises the protective effects of propofol against TNF-α stimulation in endothelial cells, primarily through PKC-β2 dependent NADPH oxidase activation.
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China ; Department of Anesthesiology, University of Hong Kong, Hong Kong.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
authors.forename: Wating
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China ; Department of Anesthesiology, University of Hong Kong, Hong Kong.
authors.forename: Huimin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
authors.forename: Zhong-yuan
authors.initials: ZY
authors.lastname: Xia
authors.affiliation: Department of Cardiac Surgery, Chongqing Zhongshan Hospital, Chongqing 400013, China.
authors.forename: Qing-jun
authors.initials: QJ
authors.lastname: Yang
authors.affiliation: Department of Anesthesia, Chongqing Zhongshan Hospital, Chongqing 400013, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Department of Anesthesia, Chongqing Zhongshan Hospital, Chongqing 400013, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Liangqing
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, University of Hong Kong, Hong Kong ; Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D010797:Phthalimides / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D009566:Nitrates; D009573:Nitrites; D010797:Phthalimides; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D064546:Protein Kinase C beta; D005996:Nitroglycerin; D015742:Propofol; C098874:4,5-dianilinophthalimide