The Mitochondrial Permeability Transition Pore and Nitric Oxide Synthase Mediate Early Mitochondrial Depolarization in Astrocytes during Oxygen–Glucose Deprivation

Background Desflurane during early reperfusion has been shown to postcondition human myocardium. Whether it involves "reperfusion injury salvage kinase" pathway remains incompletely studied. The authors tested the involvement of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, glycogen synthase kinase (GSK)-3beta, and mitochondrial permeability transition pore in desflurane-induced postconditioning. Methods The authors recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode's solution (34 degrees C, stimulation frequency 1 Hz). After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of rapamycin, a 70-kDa ribosomal protein S6 kinase inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, and atractyloside, the mitochondrial permeability transition pore opener. GSK-3beta inhibitor VII was administered during the first few minutes of reoxygenation alone or in the presence of desflurane 6%, rapamycin, NG-nitro-L-arginine methyl ester, and atractyloside. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD). Phosphorylation of GSK-3beta was measured using blotting. Results Desflurane 6% (84 +/- 4% of baseline) enhanced the recovery of force after 60 min of reoxygenation when compared with the control group (54 +/- 4%, P < 0.0001). Rapamycin (68 +/- 8% of baseline), NG-nitro-L-arginine methyl ester (57 +/- 8%), atractyloside (52 +/- 7%) abolished desflurane-induced postconditioning (P < 0.001). GSK-3beta inhibitor-induced postconditioning (84 +/- 5%, P < 0.0001 vs. control) was not modified by desflurane (78 +/- 6%), rapamycin (81 +/- 6%), and NG-nitro-L-arginine methyl ester (82 +/- 10%), but it was abolished by atractyloside (49 +/- 6%). Desflurane increased the phosphorylation of GSK-3beta (3.30 +/- 0.57-fold increase in desflurane vs. control; P < 0.0001). Conclusions In vitro, desflurane-induced postconditioning protects human myocardium through the activation of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, inhibition, and phosphorylation of GSK-3beta, and preventing mitochondrial permeability transition pore opening.

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Neuroglobin overexpression inhibits oxygen–glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons

Neurobiology of Disease ◽

10.1016/j.nbd.2013.04.015 ◽

2013 ◽

Vol 56 ◽

pp. 95-103 ◽

Cited By ~ 52

Author(s):

Zhanyang Yu ◽

Ning Liu ◽

Yadan Li ◽

Jianfeng Xu ◽

Xiaoying Wang

Keyword(s):

Cortical Neurons ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Mitochondrial Permeability ◽

Permeability Transition Pore Opening ◽

Pore Opening

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L-arginine and Tetrahydrobiopterin Inhibit Mitochondrial Permeability Transition Pore by Preventing ROS Formation by Mitochondrial Nitric Oxide Synthase

Biophysical Journal ◽

10.1016/j.bpj.2008.12.2756 ◽

2009 ◽

Vol 96 (3) ◽

pp. 534a

Author(s):

Elena N. Dedkova ◽

Lothar A. Blatter

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Mitochondrial Permeability ◽

Mitochondrial Nitric Oxide Synthase ◽

Ros Formation ◽

Oxide Synthase

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Participation of the mitochondrial permeability transition pore in nitric oxide-induced plant cell death

FEBS Letters ◽

10.1016/s0014-5793(01)03230-6 ◽

2001 ◽

Vol 510 (3) ◽

pp. 136-140 ◽

Cited By ~ 61

Author(s):

Elzira E. Saviani ◽

Cintia H. Orsi ◽

Jusceley F.P. Oliveira ◽

Cecı́lia A.F. Pinto-Maglio ◽

Ione Salgado

Keyword(s):

Nitric Oxide ◽

Cell Death ◽

Plant Cell ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Mitochondrial Permeability

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Mechanisms Involved in Cardioprotective Effects of Pravastatin Administered during Reoxygenation in Human Myocardium In Vitro

Anesthesiology ◽

10.1097/aln.0b013e31824be77c ◽

2012 ◽

Vol 116 (4) ◽

pp. 824-833 ◽

Cited By ~ 5

Author(s):

Sandrine Lemoine ◽

Stéphane Allouche ◽

Laurent Coulbault ◽

Valérie Cornet ◽

Massimo Massetti ◽

...

Keyword(s):

Caspase 3 ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Human Myocardium ◽

Control Group ◽

Force Of Contraction ◽

Mitochondrial Permeability ◽

Oxide Synthase

Background The authors investigated the effect of pravastatin during reoxygenation after myocardial hypoxia and examined the involvement of nitric oxide synthase, mitochondrial permeability transition pore, and expression of markers of apoptosis in human myocardium in vitro. Methods Human atrial trabeculae were exposed to hypoxia for 30 min and reoxygenation for 60 min (control group; n = 10). Pravastatin (5, 10, 50, 75 μM; n = 6 in each group) was administered throughout the reoxygenation. In separate groups (n = 6 in each group), pravastatin 50 μM was administered in the presence of 200 μM L-NG-nitroarginine methyl ester, a nitric oxide synthase inhibitor, and 50 μM atractyloside, the mitochondrial permeability transition pore opener. The primary endpoint was the developed force of contraction at the end of reoxygenation, expressed as a percentage of baseline (mean ± SD). Protein expression of BAD, phospho-BAD, caspase 3, Pim-1 kinase, and Bcl-2 were measured using Western immunoblotting. Results The administration of 10 (77 ± 5% of baseline), 50 (86 ± 6%), and 75 μM (88 ± 13%) pravastatin improved the force of contraction at the end of reoxygenation, compared with that of the control group (49 ± 11%; P < 0.001). These beneficial effects were prevented by L-NG-nitroarginine methyl ester and atractyloside. Compared with control group, the administration of 5 μM pravastatin did not modify the force of contraction. Pravastatin increased the phosphorylation of BAD, activated the expression of Pim-1 kinase and Bcl-2, and maintained the caspase 3 concentration relative to that of the respective untreated controls. Conclusions Pravastatin, administered at reoxygenation, protected the human myocardium by preventing the mitochondrial permeability transition pore opening, phosphorylating BAD, activating nitric oxide synthase, Pim-1 kinase, and Bcl-2, and preserving the myocardium against the caspase 3 activation.

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Astragaloside IV Inhibits Oxidative Stress-Induced Mitochondrial Permeability Transition Pore Opening by Inactivating GSK-3βvia Nitric Oxide in H9c2 Cardiac Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/935738 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Yonggui He ◽

Jinkun Xi ◽

Huan Zheng ◽

Yidong Zhang ◽

Yuanzhe Jin ◽

...

Keyword(s):

Nitric Oxide ◽

Reperfusion Injury ◽

Mitochondrial Permeability Transition Pore ◽

Mitochondrial Permeability Transition ◽

Permeability Transition Pore ◽

Permeability Transition ◽

H9c2 Cells ◽

Astragaloside Iv ◽

Mitochondrial Permeability ◽

Mptp Opening

Objective. This study aimed to investigate whether astragaloside IV modulates the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3β(GSK-3β) in H9c2 cells.Methods. H9c2 cells were exposed to astragaloside IV for 20 min. GSK-3β(Ser9), Akt (Ser473), and VASP (Ser239) activities were determined with western blot. The mPTP opening was evaluated by measuring mitochondrial membrane potential (ΔΨm). Nitric oxide (NO) generation was measured by 4-amino-5-methylamino-2′,7′-difluorofluorescein (DAF-FM) diacetate. Fluorescence images were obtained with confocal microscopy.Results. Astragaloside IV significantly enhanced GSK-3βphosphorylation and prevented H2O2-induced loss ofΔΨm. These effects of astragaloside IV were reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the NO sensitive guanylyl cyclase selective inhibitor ODQ, and the PKG inhibitor KT5823. Astragaloside IV activated Akt and PKG. Astragaloside IV was also shown to increase NO production, an effect that was reversed by L-NAME and LY294002. Astragaloside IV applied at reperfusion reduced cell death caused by simulated ischemia/reperfusion, indicating that astragaloside IV can prevent reperfusion injury. Conclusions. These data suggest that astragaloside IV prevents the mPTP opening and reperfusion injury by inactivating GSK-3βthrough the NO/cGMP/PKG signaling pathway. NOS is responsible for NO generation and is activated by the PI3K/Akt pathway.

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