scholarly journals Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores

2016 ◽  
Vol 39 (5) ◽  
pp. 1930-1940 ◽  
Author(s):  
Zuolei Chen ◽  
Donat R. Spahn ◽  
Xuewei Zhang ◽  
Yingzhi Liu ◽  
Haichen Chu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Protective Effects ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Extracellular Signal ◽  
Rat Hearts ◽  
Cyt C

Background/Aims: The purpose of this study was to investigate the implications of protein kinase C-epsilon (PKCε), Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and mitochondrial permeability transition pore (mPTP) in myocardial protection induced by morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of eight groups. Hearts in time control (TC) group were constantly perfused for 105min. Hearts in ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. εV1-2 (an inhibitor of PKCε) and PD (an inhibitor of ERK1/2) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. I/R injury was assessed by functional parameters, creatine kinase-MB (CK-MB) release and infarct size (IS/AAR). Additional hearts were excised at 20 min following reperfusion to detect the membrane-specific translocation of PKCε, ERK1/2 phosphorylation, mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) release. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of εV1-2 or PD. Compared to TC group, the membrane translocation of PKCε, ERK1/2 phosphorylation, mPTP opening, and Cyt-c release were significantly increased in I/R hearts. MpostC further increased the membrane translocation of PKCε and ERK1/2 phosphorylation, and significantly inhibited mPTP opening and Cyt-c release. However, those protective effects induced by MpostC were abolished by εV1-2 or PD, which, used alone, showed no influence on reperfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against ischemia-reperfusion injury via activating PKCε-ERK1/2 pathway and inhibiting mPTP opening.

Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury

2009 ◽  
Vol 296 (4) ◽  
pp. H1125-H1132 ◽  
Author(s):  
Masao Saotome ◽  
Hideki Katoh ◽  
Yasuhiro Yaguchi ◽  
Takamitsu Tanaka ◽  
Tsuyoshi Urushida ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Rat Hearts ◽  
Perfused Rat Hearts

Reactive oxygen species (ROS) production during ischemia-reperfusion (I/R) is thought to be a critical factor for myocardial injury. However, a small amount of ROS during the ischemic preconditioning (IPC) may provide a signal for cardioprotection. We have previously reported that the repetitive pretreatment of a small amount of ROS [hydrogen peroxide (H2O2), 2 μM] mimicked the IPC-induced cardioprotection in the Langendorff-perfused rat hearts. We further investigated the mechanisms of the ROS-induced cardioprotection against I/R injury and tested the hypothesis whether it could mediate the mitochondrial permeability transition pore (mPTP) opening. The Langendorff-perfused rat hearts were subjected to 35 min ischemia and 40 min reperfusion, and the pretreatment of H2O2 (2 μM) significantly improved the postischemic recoveries in left ventricular developed pressure, intracellular phosphocreatine, and ATP levels. A specific mPTP inhibitor cyclosporin A (CsA; 0.2 μM) canceled these H2O2-induced effects. In isolated permeabilized myocytes, H2O2 (1 μM) accelerated the calcein leakage from mitochondria in a CsA-sensitive manner, indicating the opening of mPTP by H2O2. However, H2O2 did not depolarize mitochondrial membrane potential (ΔΨm) even in the presence of oligomycin (F1/F0 ATPase inhibitor; 1 μM) and decreased mitochondrial Ca2+ concentration ([Ca2+]m) by accelerating the mitochondrial Ca2+ extrusion via an mPTP. We conclude that the transient mPTP opening could be involved in the H2O2-induced cardioprotection against reperfusion injury, and the reduction of [Ca2+]m without the change in ΔΨm might be a possible mechanism for the protection.

Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening

2009 ◽  
Vol 297 (4) ◽  
pp. H1487-H1493 ◽  
Author(s):  
Giuseppe Petrosillo ◽  
Giuseppe Colantuono ◽  
Nicola Moro ◽  
Francesca M. Ruggiero ◽  
Edy Tiravanti ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Melatonin, a well-known antioxidant, has been shown to protect against ischemia-reperfusion myocardial damage. Mitochondrial permeability transition pore (MPTP) opening is an important event in cardiomyocyte cell death occurring during ischemia-reperfusion and therefore a possible target for cardioprotection. In the present study, we tested the hypothesis that melatonin could protect heart against ischemia-reperfusion injury by inhibiting MPTP opening. Isolated perfused rat hearts were subjected to global ischemia and reperfusion in the presence or absence of melatonin in a Langerdoff apparatus. Melatonin treatment significantly improves the functional recovery of Langerdoff hearts on reperfusion, reduces the infarct size, and decreases necrotic damage as shown by the reduced release of lactate dehydrogenase. Mitochondria isolated from melatonin-treated hearts are less sensitive than mitochondria from reperfused hearts to MPTP opening as demonstrated by their higher resistance to Ca2+. Similar results were obtained following treatment of ischemic-reperfused rat heart with cyclosporine A, a known inhibitor of MPTP opening. In addition, melatonin prevents mitochondrial NAD+ release and mitochondrial cytochrome c release and, as previously shown, cardiolipin oxidation associated with ischemia-reperfusion. Together, these results demonstrate that melatonin protects heart from reperfusion injury by inhibiting MPTP opening, probably via prevention of cardiolipin peroxidation.

scholarly journals Morphine Postconditioning Protects against Reperfusion Injury via Inhibiting JNK/p38 MAPK and Mitochondrial Permeability Transition Pores Signaling Pathways

2016 ◽  
Vol 39 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Zuolei Chen ◽  
Xuewei Zhang ◽  
Yingzhi Liu ◽  
Zhongkai Liu
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathways ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Amino Terminal ◽  
Rat Hearts ◽  
Cyt C ◽  
Permeability Transition Pores ◽  
Isolated Rat

Background: The purpose of this study was to determine whether c-jun NH2 amino-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK) were involved in morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of the following groups. Hearts in the time control (TC) group were constantly perfused for 105min. Hearts in the ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. Anisomycin (an activator of JNK/p38 kinases) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. Mitochondria and cytosolic proteins were prepared to detect mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) respectively. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of anisomycin. I/R significantly increased the phosphorylation of JNK and p38 kinases, mitochondrial permeability transition (MPT) opening and Cyt-c release, while these effects were partly abolished by MpostC. The inhibitory effects of MpostC on the phosphorylation of JNK/p38 kinases, MPT opening and Cyt-c release were totally reversed by Anisocycin, which, used individually, did not show any influence on perfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against reperfusion injury via inhibiting JNK/p38 MAPKs and mitochondrial permeability transition pores signaling pathways.

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.

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.

Fas-independent mitochondrial damage triggers cardiomyocyte death after ischemia-reperfusion

2005 ◽  
Vol 289 (5) ◽  
pp. H2153-H2158 ◽  
Author(s):  
L. Gomez ◽  
N. Chavanis ◽  
L. Argaud ◽  
L. Chalabreysse ◽  
O. Gateau-Roesch ◽  
...  
Keyword(s):  
Infarct Size ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Minor Role ◽  
Mitochondrial Permeability ◽  
Mptp Opening

The Fas/Fas ligand and mitochondria pathways have been involved in cell death in several cell types. We combined the genetic inactivation of the Fas receptor ( lpr mice), on the one hand, to the pharmacological inhibition of the mitochondrial permeability transition pore (mPTP), on the other hand, to investigate which of these pathways is predominantly activated during prolonged ischemia-reperfusion. Anesthetized C57BL/6JICO (control) and C57BL/6- lpr mice were pretreated with either saline or cyclosporin A (CsA; 40 mg/kg, 3 times a day), an inhibitor of the mPTP, and underwent 25 min of ischemia and 24 h of reperfusion. After 24 h of reperfusion, hearts were harvested: infarct size was assessed by 2,3,5-triphenyltetrazolium chloride staining, myocardial apoptosis by caspase 3 activity, and mitochondrial permeability transition by Ca2+-induced mPTP opening using a potentiometric approach. Infarct size was comparable in untreated control and lpr mice, ranging from 77 ± 5% to 83 ± 3% of the area at risk. CsA significantly reduced infarct size in control and lpr hearts. Control and lpr hearts exhibited comparable increase in caspase 3 activity that averaged 57 ± 18 and 49 ± 5 pmol·min−1·mg−1, respectively. CsA treatment significantly reduced caspase 3 activity in control and lpr hearts. The Ca2+ overload required to open the mPTP was decreased to a similar extent in lpr and controls. CsA significantly attenuated Ca2+-induced mPTP opening in both groups. Our results suggest that the Fas pathway likely plays a minor role, whereas mitochondria are preferentially involved in mice cardiomyocyte death after a lethal ischemia-reperfusion injury.

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.

Abstract 342: Increased Mitochondrial Permeability Transition Pore Opening Dominates Ischemia-Reperfusion Injury in the Aged Female Rat Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Alexandra M Machikas ◽  
James C Hunter ◽  
Veronica Lopez ◽  
Donna H Korzick
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Menopausal Women ◽  
Post Menopausal

Background: Cardiovascular disease remains the leading cause of death in older post-menopausal women. Ischemia/Reperfusion (I/R) injury triggers mitochondrial calcium (Ca 2+ ) overload inducing mitochondrial permeability transition pore (MPTP) opening, mitochondrial dysfunction, and cell death potentially by necrosis, apoptosis, and/or autophagy. Purpose: We sought to determine if age-associated estrogen deficiency increases mitochondrial Ca 2+ sensitivity, providing a possible mechanism for increased vulnerability to I/R injury in older women. Methods: Mitochondrial respiration (MR) was assessed in isolated mitochondria from ventricles of adult (6 mo; n=15) and aged (24 mo; n=18) ovary-intact or ovariectomized (OVX) female F344 rats. MR at complexes I and II was compared in the absence (State 2) and presence (State 3) of ADP to calculate respiratory control index (RCI; state3/state 2). Reduced RCI following Ca 2+ addition was used to assess Ca 2+ sensitivity, while mitochondrial Ca 2+ retention capacity was measured to quantify MPTP opening (CRC; n=4-5/group) prior to and following coronary artery ligation (55 min I and 6 hr R). Apoptosis was examined using DNA laddering and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Markers of autophagy were evaluated by western blotting and mitochondrial morphology through electron microscopy (EM). Results: Significant age-dependent decreases in RCI for complex I (12%) and complex II (8%) were observed in the absence of Ca 2+ , and correlated with increased necrosis in aged hearts revealed by triphenyltetrazolium chloride (TTC) staining (p < 0.05). Ca 2+ exposure decreased MR (18-30%; p < 0.05) in Complex I of aged and OVX mitochondria vs adults. Furthermore, CRC worsened with age requiring less Ca 2+ to open the MPTP. Reduced DNA laddering and TUNEL staining combined with increased beclin-1 and cathepsinD expression in aged vs. adult further support a dominant role for necrosis over apoptosis underlying cell death in aged females (n=4-5/group). EM revealed morphological alterations with age and OVX. Conclusion: Decreased MR and increased MPTP opening with aging are likely causal in necrotic cell death mechanisms associated with I/R injury observed in post-menopausal women.

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