Published online before print July 8, 2004, doi: 10.1161/01.RES.0000138303.76488.fe
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Report |
Postconditioning: A Form of "Modified Reperfusion" Protects the Myocardium by Activating the Phosphatidylinositol 3-Kinase-Akt Pathway
From The Hatter Institute and Centre for Cardiology, University College London Hospital, London, UK.
Correspondence to Derek M. Yellon, PhD, DSc Hon FRCP, The Hatter Institute and Centre for Cardiology, University College London Hospital, Grafton Way, London, WC1E 6DB, UK. E-mail hatter-institute{at}ucl.ac.uk
Abstract
Brief intermittent episodes of ischemia and reperfusion, at the onset of reperfusion after a prolonged period of ischemia, confer cardioprotection, a phenomenon termed "ischemic postconditioning" (Postcond). We hypothesized that this phenomenon may just represent a modified form of reperfusion that activates the reperfusion injury salvage kinase (RISK) pathway. Isolated perfused rat hearts were subjected to: (a) 35 minutes of ischemia and 120 minutes of reperfusion, and infarct size was determined by tetrazolium staining; or (b) 35 minutes of ischemia and 7 minutes of reperfusion, and the phosphorylation states of Akt, endothelial NO synthase (eNOS), and p70S6K were determined. Postcond reduced infarct size from 51.2±3.4% to 31.5±4.1% (P<0.01), an effect comparable with ischemic preconditioning (IPC; 27.5±2.3%; P<0.01). Of interest, the combined protective effects of IPC and Postcond were not additive (30.1±4.8% with IPC+Postcond; P=NS). Inhibiting phosphatidylinositol 3-kinase (PI3K) at reperfusion using LY or Wortmannin (Wort) during the first 15 minutes of reperfusion completely abolished Postcond-induced protection (31.5±4.1% with Postcond versus 51.7±4.5% with Postcond+LY, P<0.01; 56.2±10.1% with Postcond+ Wort; P<0.01), suggesting that Postcond protects the heart by activating PI3K-Akt. Western blot analysis demonstrated that Postcond induced a significant increase in phosphorylation of Akt, eNOS, and p70S6K in an LY- and Wort-sensitive manner. In conclusion, we show for the first time that ischemic Postcond protects the myocardium by activating the prosurvival kinases PI3K-Akt, eNOS, and p70S6K in accordance with the RISK pathway.
Key Words: ischemia • cardioprotection • reperfusion • postconditioning • kinases
The protection afforded by ischemic preconditioning (IPC), in which short periods of ischemia protect the myocardium against a subsequent lethal ischemic insult, can only be used if the IPC mimetic is applied before the index ischemic episode.1 The index ischemic episode is often unpredictable clinically, therefore, the ability to protect the heart by intervening at the time of reperfusion provides an approach that is more suited to the clinical scenario.
The phenomenon of ischemic postconditioning (Postcond), first described by Vinten-Johansen’s group,2 in which brief intermittent repetitive interruptions to reperfusion at the onset of reperfusion after a prolonged period of ischemia reduced myocardial injury to an extent comparable to IPC, offers a novel approach to myocardial protection. Suggested mechanisms of protection include a reduction in neutrophil accumulation and decreased endothelial dysfunction,2 attenuation of oxidative stress,3 a reduction in apoptotic cell death, and attenuation of mitochondrial calcium accumulation.4
Activation of the prosurvival kinase phosphatidylinositol 3-kinase (PI3K)-Akt and the mitogen-activated protein kinase p44/p42 extracellular signal-regulated kinase (ERK) 1/2 at the time of reperfusion together comprise the cardioprotective reperfusion injury salvage kinase (RISK) pathway.5 We hypothesize that ischemic Postcond protects the heart by activating the RISK pathway, specifically the PI3K-Akt pathway, in the first few minutes of reperfusion.
Methods
Male Sprague-Dawley rats (270 to 450 g; n=103) were obtained from Charles River UK Limited (Margate, UK), and received humane care in accordance with the Home Office Guidance on the Operation of Animals (Scientific Procedures) Act of 1986 (Her Majesty’s Stationery Office, London, UK).
Isolated Perfused Rat Heart
Hearts were excised rapidly and mounted on a Langendorff perfusion system. All hearts were subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion as described previously.6 Hearts were assigned randomly to 1 of the following groups: (1) control (n=11) or control with 0.02% dimethyl sulfoxide (DMSO) vehicle (n=4) for the first 15 minutes of reperfusion; (2) IPC (n=11), comprising 2 cycles of 5 minutes of global ischemia followed by 10 minutes of reperfusion before the index ischemia; (3) Postcond (n=10), comprising 6 cycles of 10 seconds of reperfusion followed by 10 seconds global ischemia immediately after the index ischemia; (4) IPC+Postcond (n=7); (5) Postcond+ LY294002 (LY; n=13); hearts with the PI3K inhibitor LY (15µmol/L),7 given for the first 15 minutes of reperfusion; (6) Control+LY (n=5), hearts with LY given for the first 15 minutes of reperfusion; (7) Postcond with the PI3K inhibitor Wortmannin (Wort; 100 nmol/L; n=7),7 given for the first 15 minutes of reperfusion; and (8) Control+Wort (n=5), hearts with Wort given for the first 15 minutes of reperfusion.
Western Blot Analysis
Hearts were subjected to 35 minutes of regional ischemia followed by 7 minutes of reperfusion. Hearts (n=5 per group) were assigned randomly to treatment groups 1, 3, and 5 to 8, as described previously. At the end of reperfusion, the ventricular tissue at risk was excised and freeze-clamped in liquid nitrogen before being stored at –80°C. Phosphorylation states of Akt (phospho-Akt, serine [Ser] 473), endothelial NO synthase (eNOS; phospho-eNOS, Ser 1177), p70s6 kinase (phospho-p70s6k, Thr 389), and total levels of Akt, eNOS, and p70S6K proteins were analyzed by SDS-PAGE immunoelectrophoresis using antibodies obtained from New England Biolabs as described previously.7 Levels of phosphorylated proteins were normalized to their total protein levels. Relative densitometry was determined using a computerized software package (NIH Image 1.63).7
Statistical Analysis
All values are expressed as mean±SEM. Infarct size and Western blot results were analyzed by 1-way ANOVA and Fisher protected test of least significant difference. Differences were considered statistically significant when P<0.05.
Results
Ischemic Postcond Activates Akt, eNOS, and p70S6K at Time of Reperfusion
Ischemic Postcond induced Akt phosphorylation (in arbitrary units; from 36.6±6.8 in vehicle control to 83.0±3.3 with Postcond; P<0.01), eNOS (from 8.9±2.1 in vehicle control to 40.2±12.5 with Postcond; P<0.01), and p70s6K (from 11.0±3.6 in vehicle control to 79.6±7.7 with Postcond; P<0.01). When the PI3K inhibitor LY or Wort was given for the first 15 minutes of reperfusion, the Postcond-induced phosphorylation was abolished: Akt (15.3±3.5), eNOS (13±7.6) and p70s6K (3.8±2.1) with LY, and Akt (38.2±3.8), eNOS (14±5.4), and p70s6K (46.1±7) with Wort (Figure 1 a through 1c).
|
Inhibiting PI3K at Time of Reperfusion Abrogates Protection Induced by Ischemic Postcond
Infarct size, represented as a percentage of the area at risk, was significantly reduced in the IPC group (control 51.2±3.4% versus IPC 27.5±2.3%; P<0.01; Figure 2). Postcond similarly reduced infarct size (control 51.2±3.4% versus Postcond 31.5±4.1%; P<0.01). The protection induced by the combination of both IPC and Postcond did not differ compared with either alone (IPC+Postcond 30.1±4.8% versus 27.5±2.3% with IPC and 31.5±4.1% with Postcond; P=NS). However, the infarct reduction afforded by Postcond was abolished completely in the presence of the PI3K inhibitor LY or Wort given during the first 15 minutes of reperfusion (31.5±4.1% with Postcond versus 51.7±4.5% with Postcond+LY, P<0.01; 56.2±10.1% with Postcond+Wort, P<0.01; Figure 2); 0.02% DMSO did not influence infarct size in control or Postcond groups (control+DMSO 49.6±9.2%; Postcond+DMSO 33.2±4%). LY or Wort did not influence infarct size in control groups (control+LY 56.8±10.5%; control+Wort 52.3±13.3%).
|
Discussion
We demonstrate for the first time in the isolated perfused rat heart that ischemic Postcond protects the heart against ischemia reperfusion injury by activating the prosurvival kinase PI3-Akt and its downstream targets eNOS and p70S6K. These data suggest that Postcond may protect the heart by recruiting the RISK pathway in the same way as insulin, bradykinin, atorvastatin, and urocortin when given during the first few minutes of reperfusion.5 Therefore, these agents may be considered to protect by "pharmacological Postcond."
Interestingly, the combined protective effects of IPC and Postcond do not appear to be additive, which is in disagreement with the findings of Downey’s group that combined IPC and Postcond in the in vivo rabbit heart induced additive protection.8 This discrepancy may be attributable to the different models of ischemia reperfusion injury used.
Ischemic Postcond, as originally described in the in vivo dog model, 2 has been observed in the in vivo rabbit8 and rat heart3 and in rat cardiomyocytes.4 The first study investigating this phenomenon implicated a reduction in neutrophil accumulation and an improvement in endothelial function as possible mechanisms of protection.2 Subsequent studies, including the study we are reporting here, have demonstrated that protection can occur in the absence of blood constituents, suggesting that Postcond may exert a direct effect on the myocyte.3
In this regard, Vinten-Johansen’s group3 demonstrated using the in vivo rat heart that Postcond attenuated the production of reactive oxygen species (ROS) immediately at reperfusion and that ischemic Postcond protection was lost if instituted after 1 minute of reperfusion. The same group demonstrated that "hypoxic Postcond" of neonatal rat myocytes resulted in less necrotic cell death, attenuated ROS production, and reduced mitochondrial calcium loading.4
Recent data have also demonstrated that the presence of either the mitogen-activated protein kinase kinase (MEK)1/2 inhibitor PD98059 or the NOS inhibitor L-NAME during Postcond in in vivo rabbit hearts can abrogate protection, suggesting that the MEK1/2-ERK1/2 cascades and NOS may be required for protection. However, in this study, it was not demonstrated that Postcond actually activated either ERK1/2 or eNOS directly.8
Opening of the mitochondrial permeability transition pore (mPTP) during the first few minutes of reperfusion has been demonstrated to mediate cell death,9 and inhibiting its opening is cardioprotective.10 We postulate that Postcond protects the heart by inhibiting mPTP opening through activation of Akt11 and eNOS12 (Figure 3).
|
The term ischemic Postcond is probably a misnomer because the word "conditioning" implies that the process prepares the myocardium for the ischemic event, as perceived in IPC. Ischemic Postcond may simply constitute a variation of controlled reperfusion, which previous studies have demonstrated to be cardioprotective.13 Therefore, ischemic Postcond may be considered a "passive process" that modifies reperfusion injury rendering the cell and mitochondria more resistant to the biochemical and metabolic perturbation that occurs in the transition from ischemia to reperfusion (Figure 3). We show that ischemic Postcond may also be an "active process" by activating prosurvival kinases such as the PI3K-Akt pathway (Figure 3) in accordance with the RISK pathway.
In conclusion, our study demonstrates that ischemic Postcond significantly reduces infarct size in isolated perfused rat hearts and that the effects of IPC and Postcond combined are not additive. In addition, we show for the first time that protection is mediated via the PI3K-Akt prosurvival signaling cascade and its downstream targets, namely, eNOS and p70s6K. Interventions such as ischemic Postcond, which target the first few minutes of reperfusion, may offer greater opportunity for protection, clinically such as at the time of thrombolysis, angioplasty, and cardiac surgery.
Acknowledgments
A.T. is supported by a project grant from the British Heart Foundation.
Footnotes
Original received March 31, 2004; first resubmission received May 11, 2004; second resubmission received June 18, 2004; accepted June 25, 2004.
References
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. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic post-conditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003; 285: H579–H588.
3. Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res. 2004; 62: 74–85.
4. Zhao ZQ, Sun HY, Wang NP, Kerendi F, Guyton RA, Vinten-Johansen J. Hypoxic post-conditioning reduces cardiomyocyte loss by inhibiting reactive oxygen species-triggered mitochondrial calcium overload. Circulation. 2003; 108 (suppl IV): 174.[CrossRef]
5. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res. 2004; 61: 448–460.
6. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003; 60: 617–625.
7. Mocanu MM, Bell RM, Yellon DM. PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning. J Mol Cell Cardiol. 2002; 34: 661–668.[CrossRef][Medline] [Order article via Infotrieve]
8. Yang X, Downey JM, Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by activation of ERK and production of nitric oxide. Circulation. 2003; 108 (suppl IV): 158.[CrossRef]
9. Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischemia, but open upon reperfusion. Biochem J. 1995; 307: 93–98.[Medline] [Order article via Infotrieve]
10. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res. 2002; 55: 534–543.
11. Tsuruta F, Masuyama N, Gotoh Y. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J Biol Chem. 2002; 277: 14040–14047.
12. Balakirev MY, Khramtsov VV, Zimmer G. Modulation of the mitochondrial permeability transition by nitric oxide. Eur J Biochem. 1997; 246: 710–718.[Medline] [Order article via Infotrieve]
13. Sato H, Jordan JE, Zhao ZQ, Sarvotham SS, Vinten-Johansen J. Gradual reperfusion reduces infarct size and endothelial injury but augments neutrophil accumulation. Ann Thorac Surg. 1997; 64: 1099–1107.
This article has been cited by other articles:
 |
|
 |
|
  O. C. Manintveld, M. t. L. Hekkert, N. T. van der Ploeg, P. D. Verdouw, and D. J. Duncker Interaction Between Pre- and Postconditioning in the In Vivo Rat Heart Experimental Biology and Medicine, November 1, 2009; 234(11): 1345 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lacerda, S. Somers, L. H. Opie, and S. Lecour Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway Cardiovasc Res, November 1, 2009; 84(2): 201 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch No RISK, no ... cardioprotection? A critical perspective Cardiovasc Res, November 1, 2009; 84(2): 173 - 175. [Full Text] [PDF]
|
|
|
|
|
|
J. Musiolik, P. van Caster, A. Skyschally, K. Boengler, P. Gres, R. Schulz, and G. Heusch Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs Cardiovasc Res, August 25, 2009; (2009) cvp271v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Fernandez, M. P. Bordone, M. S. Chianelli, and R. E. Rosenstein Retinal Neuroprotection against Ischemia-Reperfusion Damage Induced by Postconditioning Invest. Ophthalmol. Vis. Sci., August 1, 2009; 50(8): 3922 - 3930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boengler, R. Schulz, and G. Heusch Loss of cardioprotection with ageing Cardiovasc Res, July 15, 2009; 83(2): 247 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gomez, B. Li, N. Mewton, I. Sanchez, C. Piot, M. Elbaz, and M. Ovize Inhibition of mitochondrial permeability transition pore opening: translation to patients Cardiovasc Res, July 15, 2009; 83(2): 226 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Granfeldt, D. J. Lefer, and J. Vinten-Johansen Protective ischaemia in patients: preconditioning and postconditioning Cardiovasc Res, July 15, 2009; 83(2): 234 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dow, A. Bhandari, and R. A. Kloner The Mechanism by Which Ischemic Postconditioning Reduces Reperfusion Arrhythmias in Rats Remains Elusive Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2009; 14(2): 99 - 103. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Kambe, R. Bessho, M. Fujii, M. Ochi, and K. Shimizu Sivelestat reduces myocardial ischemia and reperfusion injury in rat hearts even when administered after onset of myocardial ischemia Interactive CardioVascular and Thoracic Surgery, June 1, 2009; 8(6): 629 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Couvreur, R. Tissier, S. Pons, M. Chenoune, X. Waintraub, A. Berdeaux, and B. Ghaleh The Ceiling Effect of Pharmacological Postconditioning with the Phytoestrogen Genistein Is Reversed by the GSK3{beta} Inhibitor SB 216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through Mitochondrial ATP-Dependent Potassium Channel Opening J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1134 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Murozono, N. Takahashi, T. Shinohara, T. Ooie, Y. Teshima, M. Hara, T. Saikawa, and H. Yoshimatsu Hyperthermia-Induced Cardioprotection Is Potentiated by Ischemic Postconditioning in Rats Experimental Biology and Medicine, May 1, 2009; 234(5): 573 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Morello, A. Perino, and E. Hirsch Phosphoinositide 3-kinase signalling in the vascular system Cardiovasc Res, May 1, 2009; 82(2): 261 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Huffmyer and J. Raphael Physiology and Pharmacology of Myocardial Preconditioning and Postconditioning Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2009; 13(1): 5 - 18. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Skyschally, P. van Caster, K. Boengler, P. Gres, J. Musiolik, D. Schilawa, R. Schulz, and G. Heusch Ischemic Postconditioning in Pigs: No Causal Role for RISK Activation Circ. Res., January 2, 2009; 104(1): 15 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. G. Edwards, M. Y. White, and S. J. Cordwell The Role of Proteomics in Clinical Cardiovascular Biomarker Discovery Mol. Cell. Proteomics, October 1, 2008; 7(10): 1824 - 1837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Bouhidel, S. Pons, R. Souktani, R. Zini, A. Berdeaux, and B. Ghaleh Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1580 - H1586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Goodman, S. E. Koch, G. A. Fuller-Bicer, and K. L. Butler Regulating RISK: a role for JAK-STAT signaling in postconditioning? Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1649 - H1656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xi, A. Das, Z.-Q. Zhao, V. F. Merino, M. Bader, and R. C. Kukreja Loss of Myocardial Ischemic Postconditioning in Adenosine A1 and Bradykinin B2 Receptors Gene Knockout Mice Circulation, September 30, 2008; 118(14_suppl_1): S32 - S37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Pagel, J. G. Krolikowski, P. F. Pratt Jr, Y. H. Shim, J. Amour, D. C. Warltier, and D. Weihrauch The Mechanism of Helium-Induced Preconditioning: A Direct Role for Nitric Oxide in Rabbits Anesth. Analg., September 1, 2008; 107(3): 762 - 768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Quinlan, A. D. T. Costa, C. L. Costa, S. V. Pierre, P. Dos Santos, and K. D. Garlid Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H953 - H961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kuno, N. V. Solenkova, V. Solodushko, T. Dost, Y. Liu, X.-M. Yang, M. V. Cohen, and J. M. Downey Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1288 - H1295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. C. Yong, S. W. Lee, C. S. Foo, K. L. Neo, X. Chen, and J.-S. Bian Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1330 - H1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kobayashi, S. Minatoguchi, S. Yasuda, N. Bao, I. Kawamura, M. Iwasa, T. Yamaki, S. Sumi, Y. Misao, H. Ushikoshi, et al. Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair Cardiovasc Res, September 1, 2008; 79(4): 611 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Xing, H. Chen, M. Zhang, D. Zhao, R. Jiang, X. Liu, and S. Zhang Ischemic Postconditioning Inhibits Apoptosis After Focal Cerebral Ischemia/Reperfusion Injury in the Rat Stroke, August 1, 2008; 39(8): 2362 - 2369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Jin, J. S. Karliner, and D. A. Vessey Ischaemic postconditioning protects isolated mouse hearts against ischaemia/reperfusion injury via sphingosine kinase isoform-1 activation Cardiovasc Res, July 1, 2008; 79(1): 134 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Kocsis, J. Pipis, V. Fekete, A. Kovacs-Simon, L. Odendaal, E. Molnar, Z. Giricz, T. Janaky, J. van Rooyen, T. Csont, et al. Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2406 - H2409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Przyklenk, M. Maynard, C. E. Darling, and P. Whittaker Aging Mouse Hearts Are Refractory to Infarct Size Reduction With Post-Conditioning J. Am. Coll. Cardiol., April 8, 2008; 51(14): 1393 - 1398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Murphy and C. Steenbergen Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury Physiol Rev, April 1, 2008; 88(2): 581 - 609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Huhn, A. Heinen, N. C. Weber, M. W. Hollmann, W. Schlack, and B. Preckel Hyperglycaemia blocks sevoflurane-induced postconditioning in the rat heart in vivo: cardioprotection can be restored by blocking the mitochondrial permeability transition pore Br. J. Anaesth., April 1, 2008; 100(4): 465 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Zatta, H. Kin, D. Yoshishige, R. Jiang, N. Wang, J. G. Reeves, J. Mykytenko, R. A. Guyton, Z.-Q. Zhao, J. L. Caffrey, et al. Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1444 - H1451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Thibault, C. Piot, P. Staat, L. Bontemps, C. Sportouch, G. Rioufol, T. T. Cung, E. Bonnefoy, D. Angoulvant, J.-F. Aupetit, et al. Long-Term Benefit of Postconditioning Circulation, February 26, 2008; 117(8): 1037 - 1044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Luo, B. Li, R. Chen, R. Huang, and G. Lin Effect of ischemic postconditioning in adult valve replacement Eur. J. Cardiothorac. Surg., February 1, 2008; 33(2): 203 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. T. Lee, M. Kim, J. H. Song, S. W. C. Chen, G. Gubitosa, and C. W. Emala Sevoflurane-mediated TGF-{beta}1 signaling in renal proximal tubule cells Am J Physiol Renal Physiol, February 1, 2008; 294(2): F371 - F378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D.T. Costa, S. V. Pierre, M. V. Cohen, J. M. Downey, and K. D. Garlid cGMP signalling in pre- and post-conditioning: the role of mitochondria Cardiovasc Res, January 15, 2008; 77(2): 344 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Piper, Y. Abdallah, S. Kasseckert, and K.-D. Schluter Sarcoplasmic reticulum-mitochondrial interaction in the mechanism of acute reperfusion injury Cardiovasc Res, January 15, 2008; 77(2): 234 - 236. [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Mentzer Jr, M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2008; 3(2008): 443 - 464. [Full Text]
|
|
|
|
|
|
L. Argaud, O. Gateau-Roesch, L. Augeul, E. Couture-Lepetit, J. Loufouat, L. Gomez, D. Robert, and M. Ovize Increased mitochondrial calcium coexists with decreased reperfusion injury in postconditioned (but not preconditioned) hearts Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H386 - H391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Hale, A. Mehra, J. Leeka, and R. A. Kloner Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H421 - H425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ferdinandy, R. Schulz, and G. F. Baxter Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning Pharmacol. Rev., December 1, 2007; 59(4): 418 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Morrison, X. L. Tan, C. Ledent, S. J. Mustafa, and P. A. Hofmann Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2523 - H2529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sato, R. Bolli, G. D. Rokosh, Q. Bi, S. Dai, G. Shirk, and X.-L. Tang The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2557 - H2564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Loukogeorgakis, R. Williams, A. T. Panagiotidou, S. K. Kolvekar, A. Donald, T. J. Cole, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister Transient Limb Ischemia Induces Remote Preconditioning and Remote Postconditioning in Humans by a KATP Channel Dependent Mechanism Circulation, September 18, 2007; 116(12): 1386 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gomez, H. Thibault, A. Gharib, J.-M. Dumont, G. Vuagniaux, P. Scalfaro, G. Derumeaux, and M. Ovize Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1654 - H1661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Taki, T. Higuchi, A. Kawashima, M. Fukuoka, D. Kayano, J. F. Tait, I. Matsunari, K. Nakajima, S. Kinuya, and H. W. Strauss Effect of Postconditioning on Myocardial 99mTc-Annexin-V Uptake: Comparison with Ischemic Preconditioning and Caspase Inhibitor Treatment J. Nucl. Med., August 1, 2007; 48(8): 1301 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Robinet, H. Millart, F. Oszust, W. Hornebeck, and G. Bellon Binding of elastin peptides to S-Gal protects the heart against ischemia/reperfusion injury by triggering the RISK pathway FASEB J, July 1, 2007; 21(9): 1968 - 1978. [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]
|
|
|
|
|
|
J. Dow and R. A. Kloner Postconditioning Does Not Reduce Myocardial Infarct Size in an In Vivo Regional Ischemia Rodent Model Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 153 - 163. [Abstract] [PDF]
|
|
|
|
|
|
S. A. Hamid, H. S. Bower, and G. F. Baxter Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2598 - H2606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies Cardiovasc Res, June 1, 2007; 74(3): 343 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Y. Vanagt, R. N. Cornelussen, T. C. Baynham, A. Van Hunnik, Q. P. Poulina, F. Babiker, J. Spinelli, T. Delhaas, and F. W. Prinzen Pacing-Induced Dyssynchrony During Early Reperfusion Reduces Infarct Size J. Am. Coll. Cardiol., May 1, 2007; 49(17): 1813 - 1819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Fulop, Z. Zhang, R. B. Marchase, and J. C. Chatham Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2227 - H2236. [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]
|
|
|
|
 |
|
 E. Shi, X. Jiang, T. Kazui, N. Washiyama, K. Yamashita, H. Terada, and A. H. M. Bashar Controlled low-pressure perfusion at the beginning of reperfusion attenuates neurologic injury after spinal cord ischemia J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 942 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujita, H. Asanuma, A. Hirata, M. Wakeno, H. Takahama, H. Sasaki, J. Kim, S. Takashima, O. Tsukamoto, T. Minamino, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H2004 - H2008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. C. Manintveld, M. te Lintel Hekkert, E. J. van den Bos, G. M. Suurenbroek, D. H. Dekkers, P. D. Verdouw, J. M. Lamers, and D. J. Duncker Cardiac effects of postconditioning depend critically on the duration of index ischemia Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1551 - H1560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Bell, J. E. Clark, D. J. Hearse, and M. J. Shattock Reperfusion kinase phosphorylation is essential but not sufficient in the mediation of pharmacological preconditioning: Characterisation in the bi-phasic profile of early and late protection Cardiovasc Res, January 1, 2007; 73(1): 153 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Doukas, W. Wrasidlo, G. Noronha, E. Dneprovskaia, R. Fine, S. Weis, J. Hood, A. DeMaria, R. Soll, and D. Cheresh Phosphoinositide 3-kinase {gamma}/{delta} inhibition limits infarct size after myocardial ischemia/reperfusion injury PNAS, December 26, 2006; 103(52): 19866 - 19871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-L. Tang, H. Sato, S. Tiwari, B. Dawn, Q. Bi, Q. Li, G. Shirk, and R. Bolli Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2308 - H2317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Couvreur, L. Lucats, R. Tissier, A. Bize, A. Berdeaux, and B. Ghaleh Differential effects of postconditioning on myocardial stunning and infarction: a study in conscious dogs and anesthetized rabbits Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1345 - H1350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Gross, A. K. Hsu, and G. J. Gross The JAK/STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3beta Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H827 - H834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. T. Lee, M. Kim, M. Jan, and C. W. Emala Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells Am J Physiol Renal Physiol, July 1, 2006; 291(1): F67 - F78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ueda, H. Takano, H. Hasegawa, Y. Niitsuma, Y. Qin, M. Ohtsuka, and I. Komuro Granulocyte Colony Stimulating Factor Directly Inhibits Myocardial Ischemia-Reperfusion Injury Through Akt-Endothelial NO Synthase Pathway Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): e108 - e113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wang, D. A. Neff, J. G. Krolikowski, D. Weihrauch, M. Bienengraeber, D. C. Warltier, J. R. Kersten, and P. S. Pagel The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesth. Analg., May 1, 2006; 102(5): 1355 - 1360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Piper, S. Kasseckert, and Y. Abdallah The sarcoplasmic reticulum as the primary target of reperfusion protection Cardiovasc Res, May 1, 2006; 70(2): 170 - 173. [Full Text] [PDF]
|
|
|
|
|
|
D. Ramzy, V. Rao, and R. D. Weisel Clinical applicability of preconditioning and postconditioning: The cardiothoracic surgeons's view Cardiovasc Res, May 1, 2006; 70(2): 174 - 180. [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Zhao and J. Vinten-Johansen Postconditioning: Reduction of reperfusion-induced injury Cardiovasc Res, May 1, 2006; 70(2): 200 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [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]
|
|
|
|
|
|
S. Philipp, X.-M. Yang, L. Cui, A. M. Davis, J. M. Downey, and M. V. Cohen Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade Cardiovasc Res, May 1, 2006; 70(2): 308 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Zatta, H. Kin, G. Lee, N. Wang, R. Jiang, R. Lust, J. G. Reeves, J. Mykytenko, R. A. Guyton, Z.-Q. Zhao, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling Cardiovasc Res, May 1, 2006; 70(2): 315 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Abdallah, A. Gkatzoflia, D. Gligorievski, S. Kasseckert, G. Euler, K.-D. Schluter, M. Schafer, H.-M. Piper, and C. Schafer Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage Cardiovasc Res, May 1, 2006; 70(2): 346 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lucchinetti, J. Feng, R. d. Silva, G. V. Tolstonog, M. C. Schaub, G. G. Schumann, and M. Zaugg Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling Physiol Genomics, April 13, 2006; 25(2): 314 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Schwartz and C. J. Lagranha Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1011 - H1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Loukogeorgakis, A. T. Panagiotidou, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister Postconditioning Protects Against Endothelial Ischemia-Reperfusion Injury in the Human Forearm Circulation, February 21, 2006; 113(7): 1015 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Abdallah and C. Schafer Insulin: An overall cardiovascular protector? Cardiovasc Res, January 1, 2006; 69(1): 4 - 6. [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Bopassa, R. Ferrera, O. Gateau-Roesch, E. Couture-Lepetit, and M. Ovize PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning Cardiovasc Res, January 1, 2006; 69(1): 178 - 185. [Abstract] [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]
|
|
|
|
|
|
S. Bae and L. Zhang Gender Differences in Cardioprotection against Ischemia/Reperfusion Injury in Adult Rat Hearts: Focus on Akt and Protein Kinase C Signaling J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1125 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Obal, S. Dettwiler, C. Favoccia, H. Scharbatke, B. Preckel, and W. Schlack The Influence of Mitochondrial KATP-Channels in the Cardioprotection of Preconditioning and Postconditioning by Sevoflurane in the Rat In Vivo Anesth. Analg., November 1, 2005; 101(5): 1252 - 1260. [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]
|
|
|
|
|
|
P. Staat, G. Rioufol, C. Piot, Y. Cottin, T. T. Cung, I. L'Huillier, J.-F. Aupetit, E. Bonnefoy, G. Finet, X. Andre-Fouet, et al. Postconditioning the Human Heart Circulation, October 4, 2005; 112(14): 2143 - 2148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Weihrauch, J. G. Krolikowski, M. Bienengraeber, J. R. Kersten, D. C. Warltier, and P. S. Pagel Morphine Enhances Isoflurane-Induced Postconditioning Against Myocardial Infarction: The Role of Phosphatidylinositol-3-Kinase and Opioid Receptors in Rabbits Anesth. Analg., October 1, 2005; 101(4): 942 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Darling, R. Jiang, M. Maynard, P. Whittaker, J. Vinten-Johansen, and K. Przyklenk Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2 Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1618 - H1626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lucchinetti, R. da Silva, T. Pasch, M. C. Schaub, and M. Zaugg Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning Br. J. Anaesth., August 1, 2005; 95(2): 140 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tsang, D. J. Hausenloy, and D. M. Yellon Myocardial postconditioning: reperfusion injury revisited Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H2 - H7. [Full Text] [PDF]
|
|
|
|
|
|
H. Kin, A. J. Zatta, M. T. Lofye, B. S. Amerson, M. E. Halkos, F. Kerendi, Z.-Q. Zhao, R. A. Guyton, J. P. Headrick, and J. Vinten-Johansen Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine Cardiovasc Res, July 1, 2005; 67(1): 124 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||