Published online before print April 5, 2004, doi: 10.1161/01.CIR.0000126294.81407.7D
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:1714-1717.)
© 2004 American Heart Association, Inc.
Brief Rapid Communications |
Transient Mitochondrial Permeability Transition Pore Opening Mediates Preconditioning-Induced Protection
From the Mitochondrial Biology Group, Department of Physiology, University College London, UK (M.D.); and The Hatter Institute and Centre for Cardiology, University College London, UK (D.H., A.W., D.Y.).
Correspondence to Prof Derek Yellon, The Hatter Institute and Centre for Cardiology, University College London, Grafton Way, WC1E 6DB, UK. E-mail hatter-institute{at}ucl.ac.uk
Received November 19, 2003; revision received February 18, 2004; accepted February 24, 2004.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Transient (low-conductance) opening of the mitochondrial permeability transition pore (mPTP) may limit mitochondrial calcium load and mediate mitochondrial reactive oxygen species (ROS) signaling. We hypothesize that transient mPTP opening and ROS mediate the protection associated with myocardial preconditioning and mitochondrial uncoupling.
Methods and Results— Isolated perfused rat hearts were subjected to 35 minutes of ischemia/120 minutes of reperfusion, and the infarct-risk-volume ratio was determined by tetrazolium staining. Inhibiting mPTP opening during the preconditioning phase with cyclosporine-A (CsA, 0.2 µmol/L) or sanglifehrin-A (SfA, 1.0 µmol/L) abolished the protection associated with ischemic preconditioning (IPC) (20.2±3.6% versus 45.9±2.5% with CsA, 49.0±7.1% with SfA; P<0.001); and pharmacological preconditioning with diazoxide (Dzx, 30 µmol/L) (22.1±2.7% versus 46.3±3.0% with CsA, 48.4±5.5% with SfA; P<0.001), CCPA (the adenosine A1-receptor agonist, 200 nmol/L) (24.9±4.5% versus 54.4±6.6% with CsA, 42.6±9.0% with SfA; P<0.001), or 2,4-dinitrophenol (DNP, the mitochondrial uncoupler, 50 µmol/L) (15.7±2.7% versus 40.8±5.5% with CsA, 34.3±3.1% with SfA; P<0.001), suggesting that mPTP opening during the preconditioning phase is required to mediate protection in these settings. Inhibiting ROS during the preconditioning protocols with N-mercaptopropionylglycine (MPG, 1 mmol/L) also abolished the protection associated with IPC (20.2±3.6% versus 47.1±3.8% with MPG; P<0.001), diazoxide (22.1±2.7% versus 56.3±3.8% with MPG; P<0.001), and DNP (15.7±2.7% versus 50.7±6.6% with MPG; P<0.001) but not CCPA (24.9±4.5% versus 26.5±8.4% with MPG; P=NS). Further experiments in adult rat myocytes demonstrated that diazoxide induced CsA-sensitive, low-conductance transient mPTP opening (represented by a 28±3% reduction in mitochondrial calcein fluorescence compared with control; P<0.01).
Conclusions— We report that the protection associated with IPC, diazoxide, and mitochondrial uncoupling requires transient mPTP opening and ROS.
Key Words: ischemia • myocardial infarction • free radicals • reperfusion
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Despite ongoing intensive investigation, the actual mechanism responsible for the powerful protective phenomenon that is ischemic preconditioning (IPC)1 has not yet been elucidated. Studies have implicated mitochondria in protective mechanisms associated with IPC. Pharmacological opening of the purported mitochondrial KATP channel2 has been demonstrated to cardioprotect by preserving mitochondrial energy production during ischemia-reperfusion.3 We and others have implicated modest mitochondrial uncoupling as a critical event in preconditioning-induced protection.4,5 Mitochondrial reactive oxygen species (ROS) release may mediate the preconditioning signal.6 We have demonstrated that the prolonged (high-conductance) mitochondrial permeability transition pore (mPTP) opening, which mediates cell death at the time of reperfusion, can be inhibited by preconditioning.7
The present study focuses on the physiological transient (low-conductance) form of mPTP opening, which does not lead to cell death8 and in fact may play several important functions that may contribute to IPC-induced protection. Transient (low-conductance) mPTP opening (1) can limit mitochondrial matrix calcium load by mediating mitochondrial calcium efflux9; (2) can be induced by mitochondrial uncoupling10; and (3) can mediate mitochondrial ROS release.11
This would suggest that low-conductance transient mPTP opening may contribute to the mechanism of IPC-induced protection. In this regard, the preconditioning mimetic diazoxide has been demonstrated to induce mPTP opening.12 On this basis, we hypothesized that both transient (low-conductance) mPTP opening and ROS, during the preconditioning phase, mediate both preconditioning and mitochondrial uncoupling–induced protection.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Isolated Perfused Rat Heart
Hearts excised from male Sprague-Dawley rats were Langendorff-perfused with Krebs-Henseleit buffer and subjected to 35 minutes of ischemia followed by 120 minutes of reperfusion, and the infarct-risk-volume ratio was determined by triphenyltetrazolium-chloride staining.7
Treatment Protocols for Infarct Studies
The hearts were treated as follows (n
6/group):
- (1) Control hearts were perfused with 0.02% DMSO or 0.005% ethanol, or Krebs-Henseleit buffer alone during stabilization.
- (2) IPC hearts were treated with two 5-minute periods of global ischemia with a 10-minute intervening reperfusion.
- (3, 4) Hearts underwent the IPC protocol in the presence of the mPTP inhibitors cyclosporine-A (CsA 0.2 µmol/L, Sigma)7 or sanglifehrin-A (SfA 1.0 µmol/L, Novartis).13
- (5) Hearts underwent IPC in the presence of N-mercaptopropionylglycine (MPG, the ROS scavenger, 1 mmol/L).14
- (6, 7) Hearts were perfused with diazoxide (Dzx, 30 µmol/L)2 for 10 minutes or the adenosine A1-receptor agonist CCPA (200 nmol/L)7 for 10 minutes (during which the hearts were paced at 300 bpm for CCPA-induced bradycardia) followed by 10 minutes of washout.
- (8–13) Hearts were preconditioned with diazoxide or CCPA in the presence of CsA/SfA/MPG.
- (14) Hearts were perfused with 2,4-dinitrophenol (DNP, a mitochondrial uncoupler, 50 µmol/L)4 for 5 minutes followed by 10 minutes of washout.
- (15–17) Hearts were perfused with DNP in the presence of CsA/SfA/MPG.
- (17–19) Hearts were perfused with CsA/SfA/MPG during stabilization.
- (2) IPC hearts were treated with two 5-minute periods of global ischemia with a 10-minute intervening reperfusion.
Model for Detecting mPTP Opening in Intact Cells
We used an established method for detecting transient (low-conductance) mPTP opening in the intact cell.12,15 Adult rat myocytes isolated by collagenase perfusion from Sprague-Dawley rats, with the use of a previously described method,16 were incubated with calcein-AM (1.0 µmol/L) and cobalt-chloride (CoCl2, 1.0 mmol/L), resulting in mitochondrial localization of calcein fluorescence. mPTP opening was indicated by a reduction in mitochondrial calcein signal (expressed as the percentage of the baseline value) and was measured over 6 randomly chosen areas in 3 different cells every 5 minutes for 25 minutes, with the use of a Zeiss-510 CLSM confocal microscope (emitting at 488 nm and detecting at 505 nm).
Cells were incubated for 20 minutes at 37°C with (1) 0.05% ethanol vehicle (n=6); (2) 0.1% DMSO vehicle (n=6); or (3) diazoxide (n=18/group;30 µmol/L) in the presence or absence of CsA (0.2 µmol/L) or 5-HD (100 µmol/L).2
Statistical Analysis
All values are expressed as mean±SEM. Infarct-risk-volume ratios and mitochondrial calcein fluorescence intensities were analyzed by 1e-way ANOVA and Fisher’s protected least significant difference test for multiple comparisons. Differences were considered significant at a value of P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Opening of the mPTP Is Required for Protection
Ischemic preconditioning, diazoxide, CCPA, or DNP reduced infarct size from 49.9±3.8% in control to 20.2±3.6% with IPC, 22.1±2.7% with diazoxide, 24.9±4.5% with CCPA, and 15.7±2.7% with DNP (P<0.001; Figure 1A). Inhibiting mPTP opening during the preconditioning protocol, with the use of CsA/SfA, abolished the protection associated with IPC (20.2±3.6% versus 45.9±2.5% with CsA, 49.0±7.1% with SfA; P<0.001; Figure 1A), diazoxide (22.1±2.7% versus 46.3±3.0% with CsA, 48.4±5.5% with SfA; P<0.001; Figure 1A), CCPA (24.9±4.5% versus 54.4±6.6% with CsA, 42.6±9.0% with SfA; P<0.001; Figure 1B), and DNP (15.7±2.7% versus 40.8±5.5% with CsA, 34.3±3.1% with SfA; P<0.001; Figure 1B), suggesting that mPTP opening is required to mediate the protection in these settings. Given alone, neither cyclosporine-A nor sanglifehrin-A influenced infarct size (43.9±1.4% in control versus 42.8±3.5% with CsA, 48.0±4.2% with SfA; P=NS; Figure 1B).
|
Reactive Oxygen Species Are Required for Protection
The presence of the ROS scavenger MPG during the preconditioning protocols abolished the protection associated with IPC (20.2±3.6% versus 47.1±3.8% with MPG; P<0.001; Figure 1A), diazoxide (22.1±2.7% versus 56.3±3.8% with MPG; P<0.001; Figure 1A), and DNP (15.7±2.7% versus 50.7±6.6% with MPG; P<0.001; Figure 1B), implicating ROS as a mediator of protection in these settings. However, MPG did not abolish the protection associated with CCPA (24.9±4.5% versus 26.5±8.4% with MPG; P<0.001; Figure 1B). MPG alone did not influence infarct size (43.9±1.4% in control versus 47.8±6.4% with MPG; P=NS; Figure 1B).
Diazoxide Induces Low-Conductance Transient mPTP Opening
Treatment of calcein-loaded myocytes with diazoxide resulted in a reduction in mitochondrial calcein fluorescence to 72±3% of baseline values (P<0.01; Figure 2), indicating that diazoxide induces low-conductance transient mPTP opening in quiescent cells. This effect of diazoxide was abolished by cyclosporine-A (the mPTP inhibitor, confirming that the reduction in mitochondrial calcein fluorescence was due to mPTP opening) and by 5-HD (the mitochondrial KATP channel blocker) (Figure 2).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We report that transient (low-conductance) mPTP opening and ROS, during the preconditioning phase, are required to mediate the protection associated with ischemic and pharmacological preconditioning and mitochondrial -uncoupling. In the infarct studies, we demonstrated that pharmacologically inhibiting mPTP opening during the preconditioning phase completely abrogated the protection associated with IPC, diazoxide, and CCPA, indicating that mPTP opening is required for protection in these settings. In the myocyte model of mPTP opening,12,15 we demonstrated that diazoxide induces transient (low-conductance) mPTP opening, confirming the findings of previous studies.12,17 We confirm that IPC and diazoxide-induced protection is ROS-dependent and found that CCPA-induced preconditioning is ROS-independent, supporting the findings of Cohen and colleagues.6
We have previously demonstrated that modest mitochondrial uncoupling is a critical event in preconditioning-induced protection.4,5 In the present study, we show that this protection can be abolished by inhibiting mPTP opening, suggesting that mPTP opening occurs downstream of mitochondrial uncoupling, which is supported by the fact that mitochondrial uncoupling can induce mPTP opening.10 Transient mPTP opening can induce mitochondrial ROS release,11 which may explain why we found mitochondrial uncoupling–induced protection to be ROS-dependent.
Transient mPTP opening during the preconditioning phase may mediate protection by (Figure 3) reducing mitochondrial calcium load9: In this regard, diazoxide has been shown to induce mitochondrial calcium efflux through mPTP opening.12 Transient mPTP opening during the preconditioning phase also may mediate protection by mediating mitochondrial ROS release/signaling11: We are undertaking further studies to determine whether preconditioning-induced mitochondrial ROS release occurs through mPTP opening.
|
Because transient mPTP opening can be induced by uncoupling, oxidation of NADH,10 and an alkaline pH,8 the preconditioning stimulus may induce transient mPTP opening by mediating uncoupling, producing mitochondrial ROS, which then oxidize NADH,10 or by increasing matrix pH through activation of the mitochondrial KATP channel.18
In conclusion, we report for the first time that IPC, diazoxide, CCPA, and mitochondrial uncoupling all protect by inducing transient mPTP opening during the preconditioning phase. Given that the adenine nucleotide translocase (ANT) is believed to be a component of the mPTP8 and the recent suggestion that the ANT forms part of the mitochondrial KATP channel,19 it would be intriguing to speculate on whether agents that reportedly protect through opening of the mitochondrial KATP channel actually protect through transient (low-conductance) opening of the mPTP.
|
Acknowledgments |
|---|
Dr Derek Hausenloy is supported by the British Heart Foundation. We thank the Wellcome Trust for funding the confocal microscope.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124–1136.
2. Garlid KD, Paucek P, Yarov-Yarovoy V, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels: possible mechanism of cardioprotection. Circ Res. 1997; 81: 1072–1082.
3. Dos Santos P, Kowaltowski AJ, Laclau MN, et al. Mechanisms by which opening the mitochondrial ATP-sensitive K(+) channel protects the ischemic heart. Am J Physiol Heart Circ Physiol. 2002; 283: H284–H295.
4. Minners J, van den Bos EJ, Yellon DM, et al. Dinitrophenol, cyclosporin A, and trimetazidine modulate preconditioning in the isolated rat heart: support for a mitochondrial role in cardioprotection. Cardiovasc Res. 2000; 47: 68–73.
5. Minners J, Lacerda L, McCarthy J, et al. Ischemic and pharmacological preconditioning in Girardi cells and C2C12 myotubes induce mitochondrial uncoupling. Circ Res. 2001; 89: 787–792.
6. Cohen MV, Yang XM, Liu GS, et al. Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels. Circ Res. 2001; 89: 273–278.
7. Hausenloy DJ, Maddock HL, Baxter GF, et al. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res. 2002; 55: 534–543.
8. Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta. 1995; 1241: 139–176.[Medline] [Order article via Infotrieve]
9. Ichas F, Jouaville LS, Mazat JP. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell. 1997; 89: 1145–1153.[CrossRef][Medline] [Order article via Infotrieve]
10. Zago EB, Castilho RF, Vercesi AE. The redox state of endogenous pyridine nucleotides can determine both the degree of mitochondrial oxidative stress and the solute selectivity of the permeability transition pore. FEBS Lett. 2000; 478: 29–33.[CrossRef][Medline] [Order article via Infotrieve]
11. Zorov DB, Filburn CR, Klotz LO, et al. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 2000; 192: 1001–1014.
12. Katoh H, Nishigaki N, Hayashi H. Diazoxide opens the mitochondrial permeability transition pore and alters Ca2+ transients in rat ventricular myocytes. Circulation. 2002; 105: 2666–2671.
13. Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem. 2002; 277: 34793–34799.
14. Yue Y, Qin Q, Cohen MV, et al. The relative order of mK(ATP) channels, free radicals and p38 MAPK in preconditioning’s protective pathway in rat heart. Cardiovasc Res. 2002; 55: 681–689.
15. Petronilli V, Miotto G, Canton M, et al. Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J. 1999; 76: 725–734.[Medline] [Order article via Infotrieve]
16. Maddock HL, Mocanu MM, Yellon DM. Adenosine A(3) receptor activation protects the myocardium from reperfusion/reoxygenation injury. Am J Physiol Heart Circ Physiol. 2002; 283: H1307–H1313.
17. Holmuhamedov EL, Wang L, Terzic A. ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria. J Physiol. 1999; 519 Pt 2: 347–360.
18. Garlid KD, Paucek P. Mitochondrial potassium transport: the K(+) cycle. Biochim Biophys Acta. 2003; 1606: 23–41.[Medline] [Order article via Infotrieve]
19. Ardehali H, Chen Z, Ko Y, et al. Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. Circulation. 2003; 108 (suppl I): I-1004.
This article has been cited by other articles:
 |
|
 |
|
  E. N. Churchill, J. C. Ferreira, P. C. Brum, L. I. Szweda, and D. Mochly-Rosen Ischaemic preconditioning improves proteasomal activity and increases the degradation of {delta}PKC during reperfusion Cardiovasc Res, November 14, 2009; (2009) cvp334v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saotome, H. Katoh, Y. Yaguchi, T. Tanaka, T. Urushida, H. Satoh, and H. Hayashi Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1125 - H1132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ishii, T. Amano, T. Matsubara, and T. Murohara Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction Circulation, December 16, 2008; 118(25): 2710 - 2718. [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch, K. Boengler, and R. Schulz Cardioprotection: Nitric Oxide, Protein Kinases, and Mitochondria Circulation, November 4, 2008; 118(19): 1915 - 1919. [Full Text] [PDF]
|
|
|
|
|
|
M. B. West, G. Rokosh, D. Obal, M. Velayutham, Y.-T. Xuan, B. G. Hill, R. J. Keith, J. Schrader, Y. Guo, D. J. Conklin, et al. Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition Circulation, November 4, 2008; 118(19): 1970 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Leshnower, S. Kanemoto, M. Matsubara, H. Sakamoto, R. Hinmon, J. H. Gorman III, and R. C. Gorman Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition Ann. Thorac. Surg., October 1, 2008; 86(4): 1286 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Prunier, Y. Kawase, D. Gianni, C. Scapin, S. B. Danik, P. T. Ellinor, R. J. Hajjar, and F. del Monte Prevention of Ventricular Arrhythmias With Sarcoplasmic Reticulum Ca2+ ATPase Pump Overexpression in a Porcine Model of Ischemia Reperfusion Circulation, August 5, 2008; 118(6): 614 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. N. Obame, C. Plin-Mercier, R. Assaly, R. Zini, J. L. Dubois-Rande, A. Berdeaux, and D. Morin Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3{beta}, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 252 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Koshkin, F. F. Dai, C. A. Robson-Doucette, C. B. Chan, and M. B. Wheeler Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic {beta}-Cells J. Biol. Chem., March 21, 2008; 283(12): 7936 - 7948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ruiz-Meana, A. Rodriguez-Sinovas, A. Cabestrero, K. Boengler, G. Heusch, and D. Garcia-Dorado Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury Cardiovasc Res, January 15, 2008; 77(2): 325 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-D. Jiao, V. Garg, B. Yang, and K. Hu Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning Cardiovasc Res, January 1, 2008; 77(1): 126 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Lim, S. M. Davidson, D. J. Hausenloy, and D. M. Yellon Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition pore Cardiovasc Res, August 1, 2007; 75(3): 530 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Kang, W. S. Park, N. Kim, J. B. Youm, M. Warda, J.-H. Ko, E. A Ko, and J. Han Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H307 - H313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Oliveira, S. Guatimosim, C. H. Castro, D. T. Galan, S. Lauton-Santos, A. M. Ribeiro, A. P. Almeida, and J. S. Cruz Abolition of reperfusion-induced arrhythmias in hearts from thiamine-deficient rats Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H394 - H401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Penna, D. Mancardi, R. Rastaldo, G. Losano, and P. Pagliaro Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling Cardiovasc Res, July 1, 2007; 75(1): 168 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Khaliulin, S. J. Clarke, H. Lin, J. Parker, M.-S. Suleiman, and A. P. Halestrap Temperature preconditioning of isolated rat hearts - a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore J. Physiol., June 15, 2007; 581(3): 1147 - 1161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Davidson and M. R. Duchen Endothelial Mitochondria: Contributing to Vascular Function and Disease Circ. Res., April 27, 2007; 100(8): 1128 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Drose, U. Brandt, and P. J. Hanley K+-independent Actions of Diazoxide Question the Role of Inner Membrane KATP Channels in Mitochondrial Cytoprotective Signaling J. Biol. Chem., August 18, 2006; 281(33): 23733 - 23739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Seubert, C. J. Sinal, J. Graves, L. M. DeGraff, J. A. Bradbury, C. R. Lee, K. Goralski, M. A. Carey, A. Luria, J. W. Newman, et al. Role of Soluble Epoxide Hydrolase in Postischemic Recovery of Heart Contractile Function Circ. Res., August 18, 2006; 99(4): 442 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Di Lisa and P. Bernardi Mitochondria and ischemia-reperfusion injury of the heart: Fixing a hole Cardiovasc Res, May 1, 2006; 70(2): 191 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Gateau-Roesch, L. Argaud, and M. Ovize Mitochondrial permeability transition pore and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 264 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Deja, K. S. Golba, M. Malinowski, K. Widenka, J. Biernat, D. Szurlej, and S. Wos Diazoxide Provides Maximal KATP Channels Independent Protection if Present Throughout Hypoxia Ann. Thorac. Surg., April 1, 2006; 81(4): 1408 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Garcia-Dorado and H. M. Piper Postconditioning: Reperfusion of "reperfusion injury" after hibernation Cardiovasc Res, January 1, 2006; 69(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
|
|
S. Lecour, N. Suleman, G. A. Deuchar, S. Somers, L. Lacerda, B. Huisamen, and L. H. Opie Pharmacological Preconditioning With Tumor Necrosis Factor-{alpha} Activates Signal Transducer and Activator of Transcription-3 at Reperfusion Without Involving Classic Prosurvival Kinases (Akt and Extracellular Signal-Regulated Kinase) Circulation, December 20, 2005; 112(25): 3911 - 3918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Cai and G. L. Semenza PTEN Activity Is Modulated During Ischemia and Reperfusion: Involvement in the Induction and Decay of Preconditioning Circ. Res., December 9, 2005; 97(12): 1351 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vinten-Johansen, D. M. Yellon, and L. H. Opie Postconditioning: A Simple, Clinically Applicable Procedure to Improve Revascularization in Acute Myocardial Infarction Circulation, October 4, 2005; 112(14): 2085 - 2088. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Davidson and D. M. Yellon The role of nitric oxide in mitochondria. Focus on "Modulation of mitochondrial Ca2+ by nitric oxide in cultured bovine vascular endothelial cells" Am J Physiol Cell Physiol, October 1, 2005; 289(4): C775 - C777. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Button, S. E Mireylees, R. Germack, and J. M Dickenson Phosphatidylinositol 3-kinase and ERK1/2 are not involved in adenosine A1, A2A or A3 receptor-mediated preconditioning in rat ventricle strips Exp Physiol, September 1, 2005; 90(5): 747 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boengler, G. Dodoni, A. Rodriguez-Sinovas, A. Cabestrero, M. Ruiz-Meana, P. Gres, I. Konietzka, C. Lopez-Iglesias, D. Garcia-Dorado, F. Di Lisa, et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning Cardiovasc Res, August 1, 2005; 67(2): 234 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Di Lisa and P. Bernardi Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition Cardiovasc Res, May 1, 2005; 66(2): 222 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-M. Cao, Q. Xia, Q. Gao, M. Chen, and T.-M. Wong Calcium-Activated Potassium Channel Triggers Cardioprotection of Ischemic Preconditioning J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 644 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Hanley, S. Drose, U. Brandt, R. A. Lareau, A. L. Banerjee, D. K. Srivastava, L. J. Banaszak, J. J. Barycki, P. P. Van Veldhoven, and J. Daut 5-Hydroxydecanoate is metabolised in mitochondria and creates a rate-limiting bottleneck for {beta}-oxidation of fatty acids J. Physiol., January 15, 2005; 562(2): 307 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Halestrap, D. Hausenloy, A. Wynne, D. M. Yellon, and M. Duchen Does the Mitochondrial Permeability Transition Have a Role in Preconditioning? * Response Circulation, September 14, 2004; 110(11): e303 - e303. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||