Nitroglycerine-Induced Nitrate Tolerance Compromises Propofol Protection of the Endothelial Cells against TNF-α: The Role of PKC-β₂and 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-β 2 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-β 2 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-β 2, 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-β 2 dependent NADPH oxidase activation.

Propofol Attenuates Small Intestinal Ischemia Reperfusion Injury through Inhibiting NADPH Oxidase Mediated Mast Cell Activation

“…Excessive production of ROS by NADPH oxidase is generally considered to be involved in the pathogenesis of inflamed tissues [ 49 ], including ischemic tissues. There are a number of NADPH homologs presented in many diverse organs, such as Nox1, Nox2 (also named as gp91 phox ), and Nox3-4 [ 50 ].…”

Dexmedetomidine Analgesia Effects in Patients Undergoing Dental Implant Surgery and Its Impact on Postoperative Inflammatory and Oxidative Stress

“…Free radicals, in turn, can increase vascular permeability, release neuropeptides (i.e., substance P), enhance inflammation, and cause further tissue damage [ 52 , 53 ]. TNF- α increased the levels of superoxide anion and MDA and then induced oxidative stress and cell toxicity [ 54 , 55 ]. A small dose of hydrogen peroxide enhances toxicity of TNF- α in inducing human vascular endothelial cell apoptosis [ 56 ].…”

Intravenous Infusion of Dexmedetomidine Combined Isoflurane Inhalation Reduces Oxidative Stress and Potentiates Hypoxia Pulmonary Vasoconstriction during One‐Lung Ventilation in Patients

“…Blood sample was collected at TLV-15 and OLV-10, OLV-20, OLV-30, and OLV-40 minutes, respectively, and then plasma was separated by centrifugation. Plasma SOD activity and MDA level were measured by using specific reagents according to the protocols provided by the manufacturer (Nanjing, Jiancheng Bioengineering Institute, China) as described [ 27 , 28 ], in which the xanthine oxidase method was used for the detection of SOD activity while the thiobarbituric acid was used as substrate for the detection of MDA [ 29 ].…”