Produção Nacional
Revisado por pares
Letter Regarding Article by Argaud et al, “Postconditioning Inhibits Mitochondrial Permeability Transition”
2005; Lippincott Williams & Wilkins; Volume: 111; Issue: 24 Linguagem: Inglês
10.1161/circulationaha.105.540468
ISSN1524-4539
AutoresHeberty Tarso Facundo, Alicia J. Kowaltowski,
Tópico(s)Anesthesia and Neurotoxicity Research
ResumoHomeCirculationVol. 111, No. 24Letter Regarding Article by Argaud et al, "Postconditioning Inhibits Mitochondrial Permeability Transition" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter Regarding Article by Argaud et al, "Postconditioning Inhibits Mitochondrial Permeability Transition" Heberty T.F. Facundo and Alicia J. Kowaltowski Heberty T.F. FacundoHeberty T.F. Facundo Department of Biochemistry, University of São Paulo, São Paulo, Brazil, and Alicia J. KowaltowskiAlicia J. Kowaltowski Department of Biochemistry, University of São Paulo, São Paulo, Brazil, Originally published21 Jun 2005https://doi.org/10.1161/CIRCULATIONAHA.105.540468Circulation. 2005;111:e442To the Editor:A recent article in Circulation1 proposes that prevention of myocardial damage by postconditioning involves the inhibition of mitochondrial permeability transition pore (mPTP) opening. We find the idea attractive and in keeping with studies implicating mPTP in postischemic damage2 but believe this study is too preliminary to prove this hypothesis.The authors present 2 main findings to support their claim. The first is that NIM811, an mPTP inhibitor, presents an effect similar to postconditioning. This finding indisputably shows that mPTP opening is involved in reperfusion injury. The results of NIM811 and postconditioning were both partial, however, and possible additive effects of both treatments were not determined. As a result, these experiments do not exclude that postconditioning can act on a pathway independent of mPTP opening.The second finding the authors present is an experiment with isolated mitochondria, which indicates that larger Ca2+ loads are required to induce Ca2+ release in postconditioned preparations. Because the experiments were conducted in mitochondria isolated after reperfusion and good isolation techniques remove damaged organelles, the authors may have selected mitochondrial populations with different propensities toward reperfusion damage. Furthermore, indicators of mitochondrial functionality such as respiratory control ratios were not measured. Mitochondrial Ca2+ uptake is driven by the electrochemical proton potential,3,4 and the differences measured may reflect changes in electron transport or membrane integrity rather than propensity toward mPTP opening.3 In fact, the authors did not demonstrate that Ca2+ release under their conditions occurs via mPTP using, for example, experiments with mPTP inhibitors added in vitro. They also do not explain why the amount of Ca2+ released appears larger than that added during the experiments, an unusual result.5The manner in which data from these experiments were analyzed is unclear. In the line tracings, Ca2+ release is gradual, and Ca2+ additions were continued after the onset of this release. As a result, the Ca2+ load necessary to open mPTP measured by the authors is questionable. Finally, Ca2+ loads, usually expressed as nanomoles of Ca2+ per milligram of protein,5 were expressed as disputable micromoles per liter per milligram of protein.In essence, we believe the authors present an interesting but still unproven hypothesis, and look forward to future discussions and studies related to the role of mPTP in postconditioning.1 Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation. 2005; 111: 194–197.LinkGoogle Scholar2 Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res. 2004; 61: 372–385.CrossrefMedlineGoogle Scholar3 Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta. 1995; 1241: 139–176.CrossrefMedlineGoogle Scholar4 Gunter KK, Gunter TE. Transport of calcium by mitochondria. J Bioenerg Biomembr. 1994; 26: 471–485.CrossrefMedlineGoogle Scholar5 Fontaine E, Ichas F, Bernardi P. A ubiquinone-binding site regulates the mitochondrial permeability transition pore. J Biol Chem. 1998; 273: 25734–25740.CrossrefMedlineGoogle ScholarcirculationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & WilkinsArgaud Laurent, , Gateau-Roesch Odile, , Raisky Olivier, , Loufouat Joseph, , Ovize Michel, , and Robert Dominique, 21062005ResponseWe thank Drs Kowaltowski and Facundo for their comments regarding our article.1 Infarct size reduction by NIM811 and postconditioning, which averaged 55% and 67% of control, respectively, is usually termed "major" rather than "partial." Whether NIM811 and postconditioning would have additive effects is a valid question. Extrapolating this putative additive benefit as a proof of a common mechanism should, however, be undertaken with caution because (1) each intervention may have a dose-response effect, with apparent cumulative protection being the result of the fact that one (or both) may not be at their optimal dosage, and (2) it may not reasonably be expected in in vivo models that infarct size may be reduced to near 0 after a 30-minute ischemic insult.Whether the isolation procedure of mitochondria caused a selection of mitochondrial populations brings into question whether Ca2+-induced mPTP opening is a consequence rather than a cause of the improved myocardial viability. We previously reported that cyclosporin A and preconditioning (as well as postconditioning; unpublished, 2005) both delayed Ca2+-induced mPTP opening, whether the ischemic insult lasted 10 (ie, fully viable myocardium) or 30 (ie, partially necrotic) minutes; this effect demonstrated that inhibition of Ca2+-induced mPTP opening by pre- or postconditioning is not a consequence but is likely a cause of improved myocardial viability.2 After 10 minutes of ischemia, isolated mitochondria looked good via electron microscopy. Respiratory control ratios ranging from 6 to 7, plus their ability to quickly capture Ca2+, indicated good functionality. In vitro exposure of isolated mitochondria to cyclosporin A or NIM811 dose-dependently inhibited abrupt Ca2+ release demonstrating it was caused by the mPTP opening.2 The amount of Ca2+ released likely includes the loaded Ca2+ plus Ca2+ accumulated within the mitochondria as a result of in vivo ischemia-reperfusion. Pilot experiments indicated that the (sometimes) gradual upward displacement of the nadir of the tracing does not correspond to the mPTP opening, but it does indicate a gradually reduced capacity of the mitochondria to capture Ca2+. Performing pulses every 60 seconds until a rapid and abrupt release of Ca2+ improved the reproducibility of this test and allowed quantification.Although further investigations are required, we believe that our study strongly suggests that inhibition of mPTP plays an important role in postconditioning. Previous Back to top Next FiguresReferencesRelatedDetailsCited By Parviz Y, Waleed M, Vijayan S, Adlam D, Lavi S, Al Nooryani A, Iqbal J and Stone G (2019) Cellular and molecular approaches to enhance myocardial recovery after myocardial infarction, Cardiovascular Revascularization Medicine, 10.1016/j.carrev.2018.05.021, 20:4, (351-364), Online publication date: 1-Apr-2019. Cardoso A, Queliconi B and Kowaltowski A (2010) Mitochondrial Reactive Oxygen Species in Myocardial Pre- and Postconditioning Studies on Cardiovascular Disorders, 10.1007/978-1-60761-600-9_5, (109-123), . Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F and Forte M (2006) The mitochondrial permeability transition from in vitro artifact to disease target, FEBS Journal, 10.1111/j.1742-4658.2006.05213.x, 273:10, (2077-2099), Online publication date: 1-May-2006. June 21, 2005Vol 111, Issue 24 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.105.540468PMID: 15967857 Originally publishedJune 21, 2005 PDF download Advertisement SubjectsAnimal Models of Human DiseaseIschemiaMyocardial Infarction
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