Mitochondrial Adenosine Triphosphate–regulated Potassium Channel Opening Acts as a Trigger for Isoflurane-induced Preconditioning by Generating Reactive Oxygen Species

2003 ◽  
Vol 98 (4) ◽  
pp. 935-943 ◽  
Author(s):  
Katsuya Tanaka ◽  
Dorothee Weihrauch ◽  
Lynda M. Ludwig ◽  
Judy R. Kersten ◽  
Paul S. Pagel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Superoxide Anion ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Superoxide Anion Production ◽  
Channel Opening ◽  
Anion Production

Background Whether the opening of mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels is a trigger or an end effector of anesthetic-induced preconditioning is unknown. We tested the hypothesis that the opening of mitochondrial K(ATP) channels triggers isoflurane-induced preconditioning by generating reactive oxygen species (ROS) in vivo. Methods Pentobarbital-anesthetized rabbits were subjected to a 30-min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive a vehicle (0.9% saline) or the selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) alone 10 min before or immediately after a 30-min exposure to 1.0 minimum alveolar concentration (MAC) isoflurane. In another series of experiments, the fluorescent probe dihydroethidium was used to assess superoxide anion production during administration of 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine (2-MPG) in the presence or absence of 1.0 MAC isoflurane. Myocardial infarct size and superoxide anion production were measured using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 19 +/- 3% (mean +/- SEM) of the left ventricular area at risk as compared to the control (38 +/- 4%). 5-HD administered before but not after isoflurane abolished this beneficial effect (37 +/- 4% as compared to 24 +/- 3%). 5-HD alone had no effect on infarct size (42 +/- 3%). Isoflurane increased fluorescence intensity. Pretreatment with N-acetylcysteine, 2-MPG, or 5-HD before isoflurane abolished increases in fluorescence, but administration of 5-HD after isoflurane only partially attenuated increases in fluorescence produced by the volatile anesthetic agent. Conclusions The results indicate that mitochondrial K(ATP) channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo.

scholarly journals Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

2002 ◽  
Vol 97 (6) ◽  
pp. 1485-1490 ◽  
Author(s):  
Katsuya Tanaka ◽  
Dorothee Weihrauch ◽  
Franz Kehl ◽  
Lynda M. Ludwig ◽  
John F. LaDisa ◽  
...  
Keyword(s):  
Infarct Size ◽  
Superoxide Anion ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Oxygen Species ◽  
Superoxide Anion Production ◽  
Anion Production

Background Reactive oxygen species (ROS) contribute to myocardial protection during ischemic preconditioning, but the role of the ROS in protection against ischemic injury produced by volatile anesthetics has only recently been explored. We tested the hypothesis that ROS mediate isoflurane-induced preconditioning in vivo. Methods Pentobarbital-anesthetized rabbits were instrumented for measurement of hemodynamics and were subjected to a 30 min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive vehicle (0.9% saline), or the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptopropionyl glycine (2-MPG; 1 mg. kg(-1).min(-1)), in the presence or absence of 1.0 minimum alveolar concentration (MAC) isoflurane. Isoflurane was administered for 30 min and then discontinued 15 min before coronary artery occlusion. A fluorescent probe for superoxide anion production (dihydroethidium, 2 mg) was administered in the absence of the volatile anesthetic or 5 min before exposure to isoflurane in 2 additional groups (n = 8). Myocardial infarct size and superoxide anion production were assessed using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 24 +/- 4% (mean +/- SEM; n = 10) of the left ventricular area at risk compared with control experiments (43 +/- 3%; n = 8). NAC (43 +/- 3%; n = 7) and 2-MPG (42 +/- 5%; n = 8) abolished this beneficial effect, but had no effect on myocardial infarct size (47 +/- 3%; n = 8 and 46 +/- 3; n = 7, respectively) when administered alone. Isoflurane increased superoxide anion production as compared with control experiments (28 +/- 12 -6 +/- 9 fluorescence units; P < 0.05). Conclusions The results indicate that ROS produced following administration of isoflurane contribute to protection against myocardial infarction in vivo.

Protein Kinase C Translocation and Src Protein Tyrosine Kinase Activation Mediate Isoflurane-induced Preconditioning In Vivo 

2004 ◽  
Vol 100 (3) ◽  
pp. 532-539 ◽  
Author(s):  
Lynda M. Ludwig ◽  
Dorothee Weihrauch ◽  
Judy R. Kersten ◽  
Paul S. Pagel ◽  
David C. Warltier
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Protein Tyrosine Kinase ◽  
Oxygen Species ◽  
Kinase C

Background The authors tested the hypotheses that protein kinase C (PKC)-specific isoform translocation and Src protein tyrosine kinase (PTK) activation play important roles in isoflurane-induced preconditioning in vivo. Methods Rats (n = 125) instrumented for measurement of hemodynamics underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion and received 0.9% saline (control); PKC inhibitors chelerythrine (5 mg/kg), rottlerin (0.3 mg/kg), or PKC-epsilonV1-2 peptide (1 mg/kg); PTK inhibitors lavendustin A (1 mg/kg) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1; 1 mg/kg); mitochondrial adenosine triphosphate-sensitive potassium channel antagonist 5-hydroxydecanote (10 mg/kg); or reactive oxygen species scavenger N-acetylcysteine (150 mg/kg) in the absence and presence of a 30-min exposure to isoflurane (1.0 minimum alveolar concentration) in separate groups. Isoflurane was discontinued 15 min before coronary occlusion (memory period). Infarct size was determined using triphenyltetrazolium staining. Immunohistochemistry and confocal microscopic imaging were performed to examine PKC translocation in separate groups of rats. Results Isoflurane significantly (P < 0.05) reduced infarct size (40 +/- 3% [n = 13]) as compared with control experiments (58 +/- 2% [n = 12]). Chelerythrine, rottlerin, PKC-epsilonV1-2 peptide, lavendustin A, PP1, 5-hydroxydecanote, and N-acetylcysteine abolished the anti-ischemic actions of isoflurane (58 +/- 2% [n = 8], 50 +/- 3% [n = 9], 53 +/- 2% [n = 9], 59 +/- 3% [n = 6], 57 +/- 3% [n = 7], 60 +/- 3% [n = 7], and 53 +/- 3% [n = 6], respectively). Isoflurane stimulated translocation of the delta and epsilon isoforms of PKC to sarcolemmal and mitochondrial membranes, respectively. Conclusions Protein kinase C-delta, PKC-epsilon, and Src PTK mediate isoflurane-induced preconditioning in the intact rat heart. Opening of mitochondrial adenosine triphosphate-sensitive potassium channels and generation of reactive oxygen species are upstream events of PKC activation in this signal transduction process.

In vivo reactive oxygen species production induced by ischemia in muscle arterioles of mice: involvement of xanthine oxidase and mitochondria

2008 ◽  
Vol 294 (2) ◽  
pp. H821-H828 ◽  
Author(s):  
Nathalie Baudry ◽  
Elisabeth Laemmel ◽  
Eric Vicaut
Keyword(s):  
Xanthine Oxidase ◽  
Superoxide Anion ◽  
Ischemia Reperfusion ◽  
Complex Iii ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Superoxide Anion Production ◽  
Anion Production

Reactive oxygen species (ROS) participate in tissue injury after ischemia-reperfusion. Their implication in leukocyte adherence and increase in permeability at the venular side of the microcirculation have been reported, but very little is known about ROS production in arterioles. The objective of this work was to evaluate, in the arteriole wall in vivo, the temporal changes in superoxide anion production during ischemia and reperfusion and to identify the source of this production. Mouse cremaster muscle was exposed to 1 h of ischemia followed by 30 min of reperfusion, and superoxide anion production was assessed by a fluorescent probe, i.e., intracellular dihydroethidium oxidation. During ischemia, we found a significant increase in dihydroethidium oxidation; however, we observed no additional increase in fluorescence during the subsequent reperfusion. This phenomenon was significantly inhibited by pretreatment with superoxide dismutase. Allopurinol (xanthine oxidase inhibitor) or stigmatellin [Qo-site (oriented toward the intermembrane space) inhibitor of mitochondrial complex III] or simultaneous administration of these two inhibitors significantly reduced superoxide production during ischemia to 80%, 88%, and 72%, respectively, of that measured in the untreated ischemia-reperfusion group. By contrast, no significant inhibition was found when NADPH oxidase was inhibited by apocynin or when mitochondrial complex I or complex II was inhibited by rotenone or thenoyltrifluoroacetone. A significant increase in ROS was found with antimycin A [Qi-site (located in the inner membrane and facing the mitochondrial matrix) inhibitor of mitochondrial complex III]. We conclude that a significant increase in ROS production occurs during ischemia in the arteriolar wall. This increased production involves both a cytoplasmic source (i.e., xanthine oxidase) and the mitochondrial complex III at the Qo site.

Reactive Oxygen Species Precede Protein Kinase C-δ Activation Independent of Adenosine Triphosphate–sensitive Mitochondrial Channel Opening in Sevoflurane-induced Cardioprotection

2004 ◽  
Vol 100 (3) ◽  
pp. 506-514 ◽  
Author(s):  
R. Arthur Bouwman ◽  
René J. P. Musters ◽  
Brechje J. van Beek-Harmsen ◽  
Jaap J. de Lange ◽  
Christa Boer
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Adenosine Triphosphate ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Pkc Delta ◽  
Kinase C ◽  
Pkc Epsilon ◽  
Channel Opening

Background In the current study, the authors investigated the distinct role and relative order of protein kinase C (PKC)-delta, adenosine triphosphate-sensitive mitochondrial K+ (mito K+(ATP)) channels, and reactive oxygen species (ROS) in the signal transduction of sevoflurane-induced cardioprotection and specifically addressed their mechanistic link. Methods Isolated rat trabeculae were preconditioned with 3.8% sevoflurane and subsequently subjected to an ischemic protocol by superfusion of trabeculae with hypoxic, glucose-free buffer (40 min) followed by 60 min of reperfusion. In addition, the acute affect of sevoflurane on PKC-delta and PKC-epsilon translocation and nitrotyrosine formation was established with use of immunofluorescent analysis. The inhibitors chelerythrine (6 microM), rottlerin (1 microM), 5-hydroxydecanoic acid sodium (100 microM), and n-(2-mercaptopropionyl)-glycine (300 microM) were used to study the particular role of PKC, PKC-delta, mito K+(ATP), and ROS in sevoflurane-related intracellular signaling. Results Preconditioning of trabeculae with sevoflurane preserved contractile function after ischemia. This contractile preservation was dependent on PKC-delta activation, mito K+(ATP) channel opening, and ROS production. In addition, on acute stimulation by sevoflurane, PKC-delta but not PKC-epsilon translocated to the sarcolemmal membrane. This translocation was inhibited by PKC inhibitors and ROS scavenging but not by inhibition of mito K+(ATP) channels. Furthermore, sevoflurane directly induced nitrosylation of sarcolemmal proteins, suggesting the formation of peroxynitrite. Conclusions In sevoflurane-induced cardioprotection, ROS release but not mito K+(ATP) channel opening precedes PKC-delta activation. Sevoflurane induces sarcolemmal nitrotyrosine formation, which might be involved in the recruitment of PKC-delta to the cell membrane.

scholarly journals Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhuochao Liu ◽  
Hongyi Wang ◽  
Chuanzhen Hu ◽  
Chuanlong Wu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Antitumor Immunity ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Specific Monoclonal Antibody ◽  
Osteosarcoma Cells ◽  
Jnk Pathway ◽  
In Vivo Experiments

AbstractIn this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of reactive oxygen species and cytochrome-c, eventually leading to mitochondrial-related apoptosis via activating JNK pathway. Nevertheless, the excessive release of reactive oxygen species also activated the protective autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related apoptosis and protective autophagy independently of the immune system, and targeting autophagy is a promising combinatorial approach to amplify its cytotoxicity.

scholarly journals Plant Extracts and Reactive Oxygen Species as Two Counteracting Agents with Anti- and Pro-Obesity Properties

2019 ◽  
Vol 20 (18) ◽  
pp. 4556 ◽  
Author(s):  
Hanna Zielinska-Blizniewska ◽  
Przemyslaw Sitarek ◽  
Anna Merecz-Sadowska ◽  
Katarzyna Malinowska ◽  
Karolina Zajdel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Plant Extracts ◽  
Complex Disease ◽  
Reactive Oxygen ◽  
Complementary Therapy ◽  
Biologically Active ◽  
Mitochondrial Activity ◽  
Oxygen Species

Obesity is a complex disease of great public health significance worldwide: It entails several complications including diabetes mellitus type 2, cardiovascular dysfunction and hypertension, and its prevalence is increasing around the world. The pathogenesis of obesity is closely related to reactive oxygen species. The role of reactive oxygen species as regulatory factors in mitochondrial activity in obese subjects, molecules taking part in inflammation processes linked to excessive size and number of adipocytes, and as agents governing the energy balance in hypothalamus neurons has been examined. Phytotherapy is the traditional form of treating health problems using plant-derived medications. Some plant extracts are known to act as anti-obesity agents and have been screened in in vitro models based on the inhibition of lipid accumulation in 3T3-L1 cells and activity of pancreatic lipase methods and in in vivo high-fat diet-induced obesity rat/mouse models and human models. Plant products may be a good natural alternative for weight management and a source of numerous biologically-active chemicals, including antioxidant polyphenols that can counteract the oxidative stress associated with obesity. This review presents polyphenols as natural complementary therapy, and a good nutritional strategy, for treating obesity without serious side effects.

scholarly journals A Novel Tetrapeptide Derivative Exhibits In Vitro Inhibition of Neutrophil-Derived Reactive Oxygen Species and Lysosomal Enzymes Release

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Sumitra Miriyala ◽  
Manikandan Panchatcharam ◽  
Meera Ramanujam ◽  
Rengarajulu Puvanakrishnan
Keyword(s):  
Reactive Oxygen Species ◽  
Superoxide Anion ◽  
Lysosomal Enzymes ◽  
Reactive Oxygen ◽  
Peptide Sequence ◽  
Ros Generation ◽  
Oxygen Species ◽  
Complement Factors

Neutrophil infiltration plays a major role in the pathogenesis of myocardial injury. Oxidative injury is suggested to be a central mechanism of the cellular damage after acute myocardial infarction. This study is pertained to the prognostic role of a tetrapeptide derivative PEP1261 (BOC-Lys(BOC)-Arg-Asp-Ser(tBu)-OtBU), a peptide sequence (39–42) of lactoferrin, studied in the modulation of neutrophil functions in vitro by measuring the reactive oxygen species (ROS) generation, lysosomal enzymes release, and enhanced expression of C proteins. The groundwork experimentation was concerned with the isolation of neutrophils from the normal and acute myocardial infarct rats to find out the efficacy of PEP1261 in the presence of a powerful neutrophil stimulant, phorbol 12-myristate 13 acetate (PMA). Stimulation of neutrophils with PMA resulted in an oxidative burst of superoxide anion and enhanced release of lysosomal enzymes and expression of complement proteins. The present study further demonstrated that the free radicals increase the complement factors in the neutrophils confirming the role of ROS. PEP1261 treatment significantly reduced the levels of superoxide anion and inhibited the release of lysosomal enzymes in the stimulated control and infarct rat neutrophils. This study demonstrated that PEP1261 significantly inhibited the effect on the ROS generation as well as the mRNA synthesis and expression of the complement factors in neutrophils isolated from infarct heart.

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