scholarly journals Gastrodin Protects Cardiomyocytes from Anoxia/Reoxygenation Injury by 14-3-3η

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Meifang Zhu ◽  
Wei Deng ◽  
Suhong Di ◽  
Mingming Qin ◽  
Dan Liu ◽  
...  
Keyword(s):  
Protective Effect ◽  
Caspase 3 ◽  
Creatine Phosphokinase ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mptp Opening ◽  
Reoxygenation Injury ◽  
Underlying Mechanisms

Gastrodin (GAS) is the major component isolated from the rhizome of the Chinese traditional medicinal herb “Tianma.” Many clinical studies have found that GAS protects cardiomyocytes in cardiovascular diseases, although the effects and underlying mechanisms on cardiovascular anoxia/reoxygenation (A/R) injury remain unknown. This study is aimed at exploring the effect of gastrodin on cardiomyocytes in A/R injury. Our results suggested that the protective effect of GAS on cardiomyocytes is associated with upregulated 14-3-3η levels. Pretreatment with GAS could increase the cell viability and decrease the activities of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). GAS could also reduce reactive oxygen species (ROS) production, inhibit mitochondrial permeability transition pore (mPTP) opening, alter the maintenance of the mitochondrial membrane potential (∆Ψm), decrease the activation of caspase-3, and finally restrain cell apoptosis. Downregulating 14-3-3η levels by transfection with siRNA14-3-3η clearly attenuated the protective effect of GAS on cardiomyocytes in A/R injury.

Abstract 168: Resveratrol Translocates Gsk-3β To Mitochondria And Protects The Heart At Reperfusion By Targeting The Mitochondrial Permeability Transition Pore

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jinkun Xi ◽  
Huihua Wang ◽  
Guillaume Chanoit ◽  
Guang Cheng ◽  
Robert A Mueller ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Risk Zone ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

Although resveratrol has been demonstrated to be cardioprotective, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. We aimed to determine if resveratrol protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3β (GSK-3β). Resveratrol (10μM) given at reperfusion reduced infarct size (12.2 ± 2.5 % of risk zone vs. 37.9 ± 3.1 % of risk zone in control, n = 6) in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion, an effect that was abrogated by the mPTP opener atractyloside (30.9 ± 8.1 % of risk zone), implying that resveratrol may protect the heart at reperfusion by modulating the mPTP opening. To define the signaling mechanism underlying the action of resveratrol, we determined GSK-3β activity by measuring its phosphorylation at Ser 9 . Resveratrol significantly enhanced GSK-3β phosphorylation upon reperfusion (225.2 ± 30.0 % of control at 5 min of reperfusion). Further experiments showed that resveratrol induces translocation of GSK-3β to mitochondria and translocated GSK-3β interacts with the mPTP component cyclophilin D but not VDAC (the voltage-dependent anion channel) or ANT (the adenine nucleotide translocator) in cardiac mitochondria. Taken together, these data suggest that resveratrol prevents myocardial reperfusion injury by targeting the mPTP opening via GSK-3β. Translocation of GSK-3β to mitochondria and its interaction with the mPTP component cyclophilin D may serve as an essential mechanism that mediates the protective effect of resveratrol on reperfusion injury.

Protectors of the mitochondrial permeability transition pore activated by iron and doxorubicin

2021 ◽  
Vol 21 ◽  
Author(s):  
Tatiana A. Fedotcheva ◽  
Nadezhda I. Fedotcheva
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Membrane Damage ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Selective Electrode ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mptp Opening ◽  
Dependent Cell

Aim: The study of action of iron, DOX, and their complex on the mitochondrial permeability transition pore (MPTP) opening and the detection of possible protectors of MPTP in the conditions close to mitochondria-dependent ferroptosis. Background: The toxicity of doxorubicin (DOX) is mainly associated with the free iron accumulation and mitochondrial dysfunction. DOX can provoke ferroptosis, iron-dependent cell death driven by the membrane damage. The mitochondrial permeability transition pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. The influence of DOX on the Ca2+ -induced opening of MPTP in the presence of iron has not yet been studied. Objective: The study was conducted on isolated liver and heart mitochondria. MPTP and succinate-ubiquinone oxidoreductase were studied as targets of DOX in mitochondria-dependent ferroptosis. Methods: The study was conducted on isolated mitochondria of the liver and heart. Changes of threshold calcium concentrations required for MPTP opening were measured by a Ca2+ selective electrode, mitochondrial membrane potential was registered by tetraphenylphosphonium (TPP+)-selective electrode, and mitochondrial swelling was recorded as a decrease in absorbance at 540 nm. The activity of succinate dehydrogenase (SDH) was determined by the reduction of the electron acceptor DCPIP. Conclusion: MPTP and the respiratory complex II are identified as the main targets of the iron-dependent action of DOX on the isolated mitochondria. All MPTP protectors tested abolished or weakened the effect of iron and a complex of iron with DOX on Ca2+ -induced MPTP opening, acting in different stages of MPTP activation. These data open new approaches to the modulation of the toxic influence of DOX on mitochondria with the aim to reduce their dysfunction

Abstract 321: Obesity Causes Enhanced Sensitivity Of The Mitochondrial Permeability Transition Pore

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Judith Bernal-Ramírez ◽  
Adriana Riojas-Hernández ◽  
Flor E Morales-Marroquín ◽  
Elvía M Domínguez-Barragán ◽  
David Rodríguez-Mier ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiac Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
H2o2 Production ◽  
Mitochondrial Permeability ◽  
Removal Capacity ◽  
Mptp Opening

Several mechanisms have been implicated in heart failure (HF) development due to obesity, including altered Ca2+ homeostasis and mitochondrial increased reactive oxygen species (ROS). Besides their metabolic role, mitochondria are important cell death regulators, since their disruption induces apoptosis. The mitochondrial permeability transition pore (MPTP) formation is key in this process. Ca2+ and ROS are known inducers of MPTP, and mitochondria are the main ROS generators. However, it has not been demonstrated that MPTP formation is involved in cardiac cell death due to obesity. Therefore, the aim of this work was to determine whether Ca2+ alterations and/or MPTP opening underlie cardiac dysfunction. We used obese Zucker fa/fa rats (32 weeks old), displaying concentric hypertrophy and cardiac dysfunction. We measured: i) Systolic and diastolic Ca2+ signaling in isolated myocytes, in basal conditions and upon β-adrenergic stimulation (β-AS), and ii) in vitro mitochondrial function: respiration, ROS production and MPTP opening. We found that the main alteration in Ca2+ signaling in fa/fa myocytes was a decrease in SERCA Ca2+ removal capacity, since Ca2+ transient amplitude and spark frequency were unchanged. Furthermore, in fa/fa myocytes, β-AS response was preserved. On the other hand, fa/fa mitochondria respiration, in state 3 decreased, but was unchanged in state 4, when glutamate/malate were used as substrate, resulting in an small decrease in respiratory control. In addition, fa/fa mitochondria were more sensitive to MPTP opening, induced by Ca2+ and carboxyatractiloside (CAT). Moreover, fa/fa mitochondria showed increased H2O2 production, and in exposed thiol groups in the adenine nucleotide translocase, a regulatory MPTP component. Since Ca2+ signaling is relatively normal in fa/fa cells, it does not seem to be the main contributor to the cardiac contractile dysfunction. However, given that fa/fa mitochondria showed decrease respiratory performance, were more susceptible to MPTP opening, and showed enhanced H2O2 production. We conclude that fa/fa mitochondria were more vulnerable to enhanced oxidative stress, causing MPTP opening, which could be exacerbated by SERCA slower Ca2+ removal capacity, leading to myocyte apoptosis.

Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening

2011 ◽  
Vol 300 (4) ◽  
pp. H1237-H1251 ◽  
Author(s):  
María C. Villa-Abrille ◽  
Eugenio Cingolani ◽  
Horacio E. Cingolani ◽  
Bernardo V. Alvarez
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Heart Mitochondria ◽  
Rat Cardiomyocytes ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Inhibition of Na+/H+ exchanger 1 (NHE1) reduces cardiac ischemia-reperfusion (I/R) injury and also cardiac hypertrophy and failure. Although the mechanisms underlying these NHE1-mediated effects suggest delay of mitochondrial permeability transition pore (MPTP) opening, and reduction of mitochondrial-derived superoxide production, the possibility of NHE1 blockade targeting mitochondria has been incompletely explored. A short-hairpin RNA sequence mediating specific knock down of NHE1 expression was incorporated into a lentiviral vector (shRNA-NHE1) and transduced in the rat myocardium. NHE1 expression of mitochondrial lysates revealed that shRNA-NHE1 transductions reduced mitochondrial NHE1 (mNHE1) by ∼60%, supporting the expression of NHE1 in mitochondria membranes. Electron microscopy studies corroborate the presence of NHE1 in heart mitochondria. Immunostaining of rat cardiomyocytes also suggests colocalization of NHE1 with the mitochondrial marker cytochrome c oxidase. To examine the functional role of mNHE1, mitochondrial suspensions were exposed to increasing concentrations of CaCl2 to induce MPTP opening and consequently mitochondrial swelling. shRNA-NHE1 transduction reduced CaCl2-induced mitochondrial swelling by 64 ± 4%. Whereas the NHE1 inhibitor HOE-642 (10 μM) decreased mitochondrial Ca2+-induced swelling in rats transduced with nonsilencing RNAi (37 ± 6%), no additional HOE-642 effects were detected in mitochondria from rats transduced with shRNA-NHE1. We have characterized the expression and function of NHE1 in rat heart mitochondria. Because mitochondria from rats injected with shRNA-NHE1 present a high threshold for MPTP formation, the beneficial effects of NHE1 inhibition in I/R resulting from mitochondrial targeting should be considered.

scholarly journals SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2+ influx, and regulation of mitochondrial permeability transition pore opening

2019 ◽  
Vol 294 (28) ◽  
pp. 10807-10818 ◽  
Author(s):  
Stephen Hurst ◽  
Ariele Baggett ◽  
Gyorgy Csordas ◽  
Shey-Shing Sheu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Spastic Paraplegia ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Permeability Transition Pore Opening ◽  
Pore Opening

The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca2+-induced mPTP opening. However, this occurs independently of cyclophilin D (cyclosporine A insensitive) rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. We found that SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter (MCU) and MCU processing regulates higher order MCU-complex formation. The results suggest that SPG7 does not constitute a core component of the mPTP but can modulate mPTP through regulation of the basal mitochondrial Ca2+ concentration.

scholarly journals L-Cystathionine Protects against Homocysteine-Induced Mitochondria-Dependent Apoptosis of Vascular Endothelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xiuli Wang ◽  
Yi Wang ◽  
Lulu Zhang ◽  
Da Zhang ◽  
Lu Bai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Caspase 3 ◽  
Mitochondrial Permeability Transition ◽  
Vascular Endothelial Cells ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Vascular Endothelial ◽  
Caspase 9 ◽  
Mitochondrial Superoxide ◽  
Mptp Opening

The study was aimed at investigating the effects of L-cystathionine on vascular endothelial cell apoptosis and its mechanisms. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. Apoptosis of vascular endothelial cells was induced by homocysteine. Apoptosis, mitochondrial superoxide anion, mitochondrial membrane potential, mitochondrial permeability transition pore (MPTP) opening, and caspase-9 and caspase-3 activities were examined. Expression of Bax, Bcl-2, and cleaved caspase-3 was tested and BTSA1, a Bax agonist, and HUVEC Bax overexpression was used in the study. Results showed that homocysteine obviously induced the apoptosis of HUVECs, and this effect was significantly attenuated by the pretreatment with L-cystathionine. Furthermore, L-cystathionine decreased the production of mitochondrial superoxide anion and the expression of Bax and restrained its translocation to mitochondria, increased mitochondrial membrane potential, inhibited mitochondrial permeability transition pore (MPTP) opening, suppressed the leakage of cytochrome c from mitochondria into the cytoplasm, and downregulated activities of caspase-9 and caspase-3. However, BTSA1, a Bax agonist, or Bax overexpression successfully abolished the inhibitory effect of L-cystathionine on Hcy-induced MPTP opening, caspase-9 and caspase-3 activation, and HUVEC apoptosis. Taken together, our results indicated that L-cystathionine could protect against homocysteine-induced mitochondria-dependent apoptosis of HUVECs.

Cardioprotection of the aged rat heart by GSK-3β inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation

2011 ◽  
Vol 300 (3) ◽  
pp. H922-H930 ◽  
Author(s):  
Jiang Zhu ◽  
Mario J. Rebecchi ◽  
Peter S. A. Glass ◽  
Peter R. Brink ◽  
Lixin Liu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Male Rats ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

It is well established that inhibition of glycogen synthase kinase (GSK)-3β in the young adult myocardium protects against ischemia-reperfusion (I/R) injury through inhibition of mitochondrial permeability transition pore (mPTP) opening. Here, we investigated age-associated differences in the ability of GSK-3β inhibitor [SB-216763 (SB)] to protect the heart and to modulate mPTP opening during I/R injury. Fischer 344 male rats were assigned from their respective young or old age groups. Animals were subjected to 30 min ischemia following 120 min reperfusion to determine myocardial infarction (MI) size in vivo. Ischemic tissues were collected 10 min after reperfusion for nicotinamide adenine dinucleotide (NAD+) measurements and immunoblotting. In parallel experiments, ventricular myocytes isolated from young or old rats were exposed to oxidative stress through generation of reactive oxygen species (ROS), and mPTP opening times were measured by using confocal microscopy. Our results showed that SB decreased MI in young SB-treated rats compared with young untreated I/R animals, whereas SB failed to significantly affect MI in the old animals. SB also significantly increased GSK-3β phosphorylation in young rats, but phosphorylation levels were already highly elevated in old control groups. There were no significant differences observed between SB-treated and untreated old animals. NAD+levels were better maintained in young SB-treated animals compared with the young untreated group during I/R, but this relative improvement was not observed in old animals. SB also significantly prolonged the time to mPTP opening induced by ROS in young cardiomyocytes, but not in aged cardiomyocytes. These results demonstrate that this GSK-3β inhibitor fails to protect the aged myocardium in response to I/R injury or prevent mPTP opening following a rise in ROS and suggest that healthy aging alters mPTP regulation by GSK-3β.

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

2012 ◽  
Vol 116 (4) ◽  
pp. 824-833 ◽  
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.

scholarly journals Antimicrobial peptide CGA-N12 decreases the Candida tropicalis mitochondrial membrane potential via mitochondrial permeability transition pore

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Ruifang Li ◽  
Jiarui Zhao ◽  
Liang Huang ◽  
Yanjie Yi ◽  
Aihua Li ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Candida Tropicalis ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Abstract Amino acid sequence from 65th to 76th residue of the N-terminus of Chromogranin A (CGA-N12) is an antimicrobial peptide (AMP). Our previous studies showed that CGA-N12 reduces Candida tropicalis mitochondrial membrane potential. Here, we explored the mechanism that CGA-N12 collapsed the mitochondrial membrane potential by investigations of its action on the mitochondrial permeability transition pore (mPTP) complex of C. tropicalis. The results showed that CGA-N12 induced cytochrome c (Cyt c) leakage, mitochondria swelling and led to polyethylene glycol (PEG) of molecular weight 1000 Da penetrate mitochondria. mPTP opening inhibitors bongkrekic acid (BA) could contract the mitochondrial swelling induced by CGA-N12, but cyclosporin A (CsA) could not. Therefore, we speculated that CGA-N12 could induce C. tropicolis mPTP opening by preventing the matrix-facing (m) conformation of adenine nucleotide transporter (ANT), thereby increasing the permeability of the mitochondrial membrane and resulted in the mitochondrial potential dissipation.

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