scholarly journals Lack of Endothelial α1AMPK Reverses the Vascular Protective Effects of Exercise by Causing eNOS Uncoupling

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1974
Author(s):  
Thomas Jansen ◽  
Miroslava Kvandová ◽  
Isabella Schmal ◽  
Sanela Kalinovic ◽  
Paul Stamm ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Exercise Training ◽  
Uncoupling Protein ◽  
Reactive Oxygen ◽  
Voluntary Exercise ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Oxygen Species ◽  
Enos Uncoupling

Voluntary exercise training is an effective way to prevent cardiovascular disease, since it results in increased NO bioavailability and decreased reactive oxygen species (ROS) production. AMP-activated protein kinase (AMPK), especially its α1AMPK subunit, modulates ROS-dependent vascular homeostasis. Since endothelial cells play an important role in exercise-induced changes of vascular signaling, we examined the consequences of endothelial-specific α1AMPK deletion during voluntary exercise training. We generated a mouse strain with specific deletion of α1AMPK in endothelial cells (α1AMPKflox/flox x TekCre+). While voluntary exercise training improved endothelial function in wild-type mice, it had deleterious effects in mice lacking endothelial α1AMPK indicated by elevated reactive oxygen species production (measured by dihydroethidum fluorescence and 3-nitrotyrosine staining), eNOS uncoupling and endothelial dysfunction. Importantly, the expression of the phagocytic NADPH oxidase isoform (NOX-2) was down-regulated by exercise in control mice, whereas it was up-regulated in exercising α1AMPKflox/flox x TekCre+ animals. In addition, nitric oxide bioavailability was decreased and the antioxidant/protective nuclear factor erythroid 2-related factor 2 (Nrf-2) response via heme oxygenase 1 and uncoupling protein-2 (UCP-2) was impaired in exercising α1AMPKflox/flox x TekCre+ mice. Our results demonstrate that endothelial α1AMPK is a critical component of the signaling events that enable vascular protection in response to exercise. Moreover, they identify endothelial α1AMPK as a master switch that determines whether the effects of exercise on the vasculature are protective or detrimental.

Interaction of electrophilic lipid oxidation products with mitochondria in endothelial cells and formation of reactive oxygen species

2006 ◽  
Vol 290 (5) ◽  
pp. H1777-H1787 ◽  
Author(s):  
Aimee Landar ◽  
Jaroslaw W. Zmijewski ◽  
Dale A. Dickinson ◽  
Claire Le Goffe ◽  
Michelle S. Johnson ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Reactive Oxygen ◽  
Direct Interaction ◽  
Oxidation Products ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Lipid Oxidation Products ◽  
Ros Formation

Electrophilic lipids, such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and 15-J2-isoprostane induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses, such as heme oxygenase-1 (HO-1) and glutathione (GSH). When we compared the ability of these distinct electrophiles to stimulate GSH and HO-1 production, the cyclopentenone electrophiles were somewhat more potent than HNE. Over the concentration range required to observe equivalent induction of GSH, dichlorofluorescein fluorescence was used to determine both the location and amounts of electrophilic lipid-dependent ROS formation in endothelial cells. The origin of the ROS on exposure to these compounds was largely mitochondrial. To investigate the possibility that the increased ROS formation was due to mitochondrial localization of the lipids, we prepared a novel fluorescently labeled form of the electrophilic lipid 15d-PGJ2. The lipid demonstrated strong colocalization with the mitochondria, an effect which was not observed by using a fluorescently labeled nonelectrophilic lipid. The role of mitochondria was confirmed by using cells deficient in functional mitochondria. On the basis of these data, we propose that ROS formation in endothelial cells is due to the direct interaction of these lipids with the organelle.

Increased reactive oxygen species production with antisense oligonucleotides directed against uncoupling protein 2 in murine endothelial cells

2002 ◽  
Vol 80 (6) ◽  
pp. 757-764 ◽  
Author(s):  
Carine Duval ◽  
Anne Nègre-Salvayre ◽  
Alain Doglio ◽  
Robert Salvayre ◽  
Luc Pénicaud ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Antisense Oligonucleotides ◽  
Uncoupling Protein ◽  
Reactive Oxygen ◽  
Ldl Oxidation ◽  
Uncoupling Protein 2 ◽  
Thiobarbituric Acid Reactive Substance ◽  
Oxygen Species

Uncoupling protein 2 (UCP-2) belongs to the mitochondrial anion carrier family. It is ubiquitously expressed but is most abdundant in the reticuloendothelial system. In addition to uncoupling function, UCP-2 modulates the production of reactive oxygen species (ROS) by isolated mitochondria. Using an antisense oligonucleotide strategy, we investigated whether a defect in UCP-2 expression modulates ROS in intact endothelial cells. Murine endothelial cells (CRL 2181) pretreated by antisense oligonucleotides directed against UCP-2 mRNA exhibited a significant and specific increase in membrane potential and intracellular ROS level compared with control scrambled or anti-UCP-1 and -UCP-3 antisense oligonucleotides. These specific changes induced by UCP-2 antisense oligonucleotides were correlated with a rise in extracellular superoxide anion production and oxidative stress assessed by thiobarbituric acid reactive substance values. Taken together, these data suggest a role for UCP-2 in control of ROS production and subsequent oxidation of surrounding compounds mediating oxidative stress of endothelial cells. These data also support the notion that manipulations of UCP-2 at the genetic level could control ROS metabolism at the cellular level.Key words: UCP-2, reactive oxygen species, LDL oxidation, oxidative stress, mitochondria, endothelial cells.

scholarly journals Mitochondria-Derived Reactive Oxygen Species Mediate Heme Oxygenase-1 Expression in Sheared Endothelial Cells

2009 ◽  
Vol 329 (1) ◽  
pp. 94-101 ◽  
Author(s):  
Zhaosheng Han ◽  
Saradhadevi Varadharaj ◽  
Randy J. Giedt ◽  
Jay L. Zweier ◽  
Hazel H. Szeto ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Heme Oxygenase ◽  
Reactive Oxygen ◽  
Heme Oxygenase 1 ◽  
Oxygen Species

Nrf2-BDNF-TrkB pathway contributes to cortical hemorrhage-induced depression, but not sex differences

2021 ◽  
pp. 0271678X2110290
Author(s):  
Honglei Ren ◽  
Ranran Han ◽  
Xi Liu ◽  
Limin Wang ◽  
Raymond C Koehler ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Production ◽  
Reactive Oxygen ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Oxygen Species ◽  
Wild Type ◽  
Post Stroke ◽  
Post Stroke Depression ◽  
Species Production

Post-stroke depression, observed in 30-50% of stroke patients, negatively affects quality of life and mortality. The pathogenesis of post-stroke depression is complex, but heightened reactive oxygen species production and inflammation might be two key factors. We have reported that intracerebral hemorrhage (ICH) in cerebral cortex produces depression-like behavior in young male mice. Here, we found that mice lacking nuclear factor erythroid-derived 2-related factor 2 (Nrf2), a transcription factor that upregulates antioxidant proteins and trophic factors such as brain-derived neurotrophic factor (BDNF), had more severe depression-like behavior than wild-type mice at days 21 to 28 after cortical ICH (c-ICH). Moreover, the expression of Nrf2, heme oxygenase-1, BDNF, and TrkB were significantly decreased in wild-type mice after c-ICH. Interestingly, TP-500 (2 mg/kg), a potent Nrf2 inducer, decreased the inflammatory response and reactive oxygen species production on day 28 after c-ICH and improved depression-like behaviors. TrkB receptor antagonist ANA-12 abolished this anti-depression effect. Depression was more severe in female than in male wild-type mice after ICH, but TP-500 improved depression-like behavior in females. These results suggest that downregulation of Nrf2-BDNF-TrkB signaling contributes to development of post-stroke depression, and that Nrf2 inducer TP-500 might improve depression after c-ICH.

scholarly journals Marine Antimicrobial Peptide TP4 Exerts Anticancer Effects on Human Synovial Sarcoma Cells via Calcium Overload, Reactive Oxygen Species Production and Mitochondrial Hyperpolarization

Marine Drugs ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 93
Author(s):  
Bor-Chyuan Su ◽  
Giun-Yi Hung ◽  
Yun-Chieh Tu ◽  
Wei-Chen Yeh ◽  
Meng-Chieh Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Antimicrobial Peptide ◽  
Anticancer Activity ◽  
Synovial Sarcoma ◽  
Uncoupling Protein ◽  
Reactive Oxygen ◽  
Calcium Overload ◽  
Oxygen Species ◽  
Sarcoma Cells

Synovial sarcoma is a rare but aggressive soft-tissue sarcoma associated with translocation t(X;18). Metastasis occurs in approximately 50% of all patients, and curative outcomes are difficult to achieve in this group. Since the efficacies of current therapeutic approaches for metastatic synovial sarcoma remain limited, new therapeutic agents are urgently needed. Tilapia piscidin 4 (TP4), a marine antimicrobial peptide, is known to exhibit multiple biological functions, including anti-bacterial, wound-healing, immunomodulatory, and anticancer activities. In the present study, we assessed the anticancer activity of TP4 in human synovial sarcoma cells and determined the underlying mechanisms. We first demonstrated that TP4 can induce necrotic cell death in human synovial sarcoma AsKa-SS and SW982 cells lines. In addition, we saw that TP4 initiates reactive oxygen species (ROS) production and downregulates antioxidant proteins, such as uncoupling protein-2, superoxide dismutase (SOD)-1, and SOD-2. Moreover, TP4-induced mitochondrial hyperpolarization is followed by elevation of mitochondrial ROS. Calcium overload is also triggered by TP4, and cell death can be attenuated by a necrosis inhibitor, ROS scavenger or calcium chelator. In our experiments, TP4 displayed strong anticancer activity in human synovial sarcoma cells by disrupting oxidative status, promoting mitochondrial hyperpolarization and causing calcium overload.

scholarly journals Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species

2021 ◽  
Vol 22 (11) ◽  
pp. 6044
Author(s):  
Xiaoling Li ◽  
Gregor Römer ◽  
Raphaela P. Kerindongo ◽  
Jeroen Hermanides ◽  
Martin Albrecht ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Reactive Oxygen ◽  
Cyclic Stretch ◽  
Cell Permeability ◽  
Ros Production ◽  
Oxygen Species ◽  
Barrier Dysfunction ◽  
Human Coronary Artery ◽  
Oxidative Effect

SGLT-2i’s exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i’s empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i’s (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i’s improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i’s might be partially mediated by inhibition of NHE1 and NOXs.

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