Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia

Borutaitė, Vilmantė; Jekabsone, Aistė; Morkūnienė, Ramunė; Brown, Guy C.

doi:10.1016/s0022-2828(03)00005-1

Cited by 171 publications

(129 citation statements)

References 41 publications

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“…mPTP has been proposed to be formed by adenine nucleotide translocase (ANT), the voltage-dependent anion channel (VDAC), and cyclophilin-D (Fig.1) (38-41). Besides being the moment of ''no-return'' for cell death in reperfusion, mPTP opening is also involved in heart failure development (17,58,127,196). The oxidative opening of mPTP is central in reperfusion injury (for reviews, see [38][39][40][41]158), and, as said, it causes mitochondrial depolarization, loss of small molecular weight substances from the matrix, and rupture of OMM (6,32,126,196).…”

Section: Mitochondrial Permeability Transition Pore Openingmentioning

confidence: 99%

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Pagliaro

Moro

Tullio

et al. 2011

Antioxidants & Redox Signaling

113

152

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Post-ischemic reperfusion may result in reactive oxygen species (ROS) generation, reduced availability of nitric oxide (NO ), Ca 2+ overload, prolonged opening of mitochondrial permeability transition pore, and other processes contributing to cell death, myocardial infarction, stunning, and arrhythmias. With the discovery of the preconditioning and postconditioning phenomena, reperfusion injury has been appreciated as a reality from which protection is feasible, especially with postconditioning, which is under the control of physicians. Potentially cooperative protective signaling cascades are recruited by both pre-and postconditioning. In these pathways, phosphorylative= dephosphorylative processes are widely represented. However, cardioprotective modalities of signal transduction also include redox signaling by ROS, S-nitrosylation by NO and derivative, S-sulfhydration by hydrogen sulfide, and O-linked glycosylation with beta-N-acetylglucosamine. All these modalities can interact and regulate an entire pathway, thus influencing each other. For instance, enzymes can be phosphorylated and=or nitrosylated in specific and=or different site(s) with consequent increase or decrease of their specific activity. The cardioprotective signaling pathways are thought to converge on mitochondria, and various mitochondrial proteins have been identified as targets of these post-transitional modifications in both pre-and postconditioning. Antioxid. Redox Signal. 14, 833-850.

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Section: Mitochondrial Permeability Transition Pore Openingmentioning

confidence: 99%

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Pagliaro

Moro

Tullio

et al. 2011

Antioxidants & Redox Signaling

113

152

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“…We and others have previously ascribed these changes to ischaemia-and/or reperfusion-induced mitochondrial permeability transition that causes cytochrome c release, which inhibits mitochondrial respiration and activates caspases that execute apoptosis (Halestrap et al, 1998;Borutaite et al, 2003). The addition of TMPD to the hearts prior to ischaemia or ischaemia/ reperfusion partially inhibited caspase activation and nuclear apoptosis without blocking cytochrome c release or the related inhibition of mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 98%

“…In general, it is found that relatively short periods of ischaemia induce apoptosis, longer periods of ischaemia induce necrosis, while reperfusion induces necrosis with additional apoptosis (Schumer et al, 1992;Fliss and Gattinger, 1996;Kametsu et al, 2003), but the relation between these events remains unclear. We and others have shown that ischaemia induces rapid cytochrome c release from mitochondria in rat perfused hearts, followed by caspase activation and nuclear apoptosis (De Moissac et al, 2000;Borutaite et al, 2001), and these events are prevented by inhibiting the mitochondrial permeability transition pore (Borutaite et al, 2003). Cytochrome c release activates apoptosis by binding to a cytosolic adaptor protein, APAF-1, which then recruits and activates procaspase-9 within the apoptosome (Li et al, 1997).…”

Section: Introductionmentioning

confidence: 98%

“…We and others have shown that ischaemia induces rapid cytochrome c release from mitochondria in rat perfused hearts, followed by caspase activation and nuclear apoptosis (De Moissac et al, 2000;Borutaite et al, 2001), and these events are prevented by inhibiting the mitochondrial permeability transition pore (Borutaite et al, 2003). Cytochrome c release activates apoptosis by binding to a cytosolic adaptor protein, APAF-1, which then recruits and activates procaspase-9 within the apoptosome (Li et al, 1997).…”

Section: Introductionmentioning

confidence: 98%

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Tetramethylphenylenediamine protects the isolated heart against ischaemia‐induced apoptosis and reperfusion‐induced necrosis

Barauskaite

Grybauskienė

Morkūnienė

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSECytochrome c when released from mitochondria into cytosol triggers assembly of the apoptosome resulting in caspase activation. Recent evidence suggests that reduced cytochrome c is unable to activate the caspase cascade. In this study, we investigated whether a chemical reductant of cytochrome c, N,N,N′,N′-tetramethylphenylene-1,4-diamine (TMPD), which we have previously shown to block cytochrome c-induced caspase activation, could prevent ischaemia-induced apoptosis in the rat perfused heart. EXPERIMENTAL APPROACHThe Langendorff-perfused rat hearts were pretreated with TMPD and subjected to stop-flow ischaemia or ischaemia/reperfusion. The activation of caspases (measured as DEVD-p-nitroanilide-cleaving activity), nuclear apoptosis of cardiomyocytes (measured by dUTP nick end labelling assay), mitochondrial and cytosolic levels of cytochrome c (measured spectrophotometrically and by ELISA), and reperfusion-induced necrosis (measured as the activity of creatine kinase released into perfusate) were assessed. KEY RESULTSWe found that perfusion of the hearts with TMPD strongly inhibited ischaemia-or ischaemia/reperfusion-induced activation of caspases and partially prevented nuclear apoptosis in cardiomyocytes. TMPD did not prevent ischaemia-or ischaemia/ reperfusion-induced release of cytochrome c from mitochondria into cytosol. TMPD also inhibited ischaemia/reperfusioninduced necrosis. CONCLUSIONS AND IMPLICATIONSThese results suggest that TMPD or related molecules might be used to protect the heart against damage induced by ischaemia/reperfusion. The mechanism of this protective effect of TMPD probably involves electron reduction of cytochrome c (without decreasing its release) which then inhibits the activation of caspases. AbbreviationsAPAF-1, apoptosis activating factor 1; TMPD, N,N,N′,N′-tetramethylphenylene-1,4-diamine; TUNEL, dUTP nick end labelling IntroductionHeart ischaemia causes myocardial infarction and heart failure, which, according to the World Health Organization, are among the most common causes of human death in the world. Heart ischaemia or heart ischaemia plus reperfusion can induce necrosis and/or apoptosis of cardiomyocytes (Ganote et al., 1975;Freude et al., 1998;Lemasters et al., 1999). In general, it is found that relatively short periods of ischaemia induce apoptosis, longer periods of ischaemia induce necrosis, while reperfusion induces necrosis with additional apoptosis (Schumer et al., 1992;Fliss and Gattinger, 1996;Kametsu et al., 2003), but the relation between these events remains unclear. We and others have shown that ischaemia induces rapid cytochrome c release from mitochondria in rat perfused hearts, followed by caspase activation and nuclear apoptosis (De Moissac et al., 2000;Borutaite et al., 2001), and these events are prevented by inhibiting the mitochondrial permeability transition pore (Borutaite et al., 2003). Cytochrome c release activates apoptosis by binding to a cytosolic adaptor protein, APAF-1, which then recruits and activates procaspase-9 w...

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“…Ca 2+ overload is the main pathological change of MIRI (31). The elevation in the intracellular Ca 2+ levels directly triggers cell death, and an increase in the mitochondrial Ca 2+ levels may induce depolarization of the inner mitochondrial membrane and the opening of mitochondrial permeability transition pores, which would give rise to adenosine triphosphate depletion and apoptosis (4,(32)(33)(34). Thus, the control of the intracellular Ca 2+ levels is a key factor in the treatment of reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol attenuates hypoxia/reoxygenation-induced Ca2+ overload by inhibiting the Wnt5a/Frizzled-2 pathway in rat H9c2 cells

Zhou

Zhu

et al. 2014

Molecular Medicine Reports

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Abstract.Resveratrol is able to protect myocardial cells from ischemia/reperfusion-induced injury. However, the mechanism has yet to be fully elucidated. In the present study, it is reported that resveratrol has a critical role in the control of Ca 2+ overload, which is the primary underlying cause of ischemia/reperfusion injury. Hypoxia/reoxygenation (H/R) treatment decreased the cell viability and increased the apoptosis of H9c2 cells, whereas the caspase-3 and intracellular Ca 2+ levels were greatly elevated compared with the control group. Treatment of H9c2 cells with resveratrol (5, 15 and 30 µM) reduced caspase-3 expression and cardiomyocyte apoptosis in a dose-dependent manner, and the intracellular Ca 2+ overload was also significantly decreased. Furthermore, Frizzled-2 and Wnt5a belong to the non-canonical Wnt/Ca 2+ pathway, which have been demonstrated to be responsible for Ca 2+ overload, and were thus detected in the present study. The results indicated that both the mRNA and protein expression levels of Frizzled-2 and Wnt5a in H/R-induced H9c2 cells were markedly increased compared with the levels found in normal cells, and treatment with resveratrol (5, 15 and 30 µM) significantly reduced the expression of Frizzled-2 and Wnt5a compared with the H/R group. The results indicated that resveratrol protected myocardial cells from H/R injury by inhibiting the Ca 2+ overload through suppression of the Wnt5a/Frizzled-2 pathway.

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Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia

Cited by 171 publications

References 41 publications

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

Tetramethylphenylenediamine protects the isolated heart against ischaemia‐induced apoptosis and reperfusion‐induced necrosis

Resveratrol attenuates hypoxia/reoxygenation-induced Ca2+ overload by inhibiting the Wnt5a/Frizzled-2 pathway in rat H9c2 cells

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