Skip Navigation


Cardiovascular Research Advance Access originally published online on November 11, 2007
Cardiovascular Research 2008 77(2):234-236; doi:10.1093/cvr/cvm066
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
77/2/234    most recent
cvm066v3
cvm066v2
cvm066v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Piper, H. M.
Right arrow Articles by Schlüter, K.-D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Piper, H. M.
Right arrow Articles by Schlüter, K.-D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Sarcoplasmic reticulum–mitochondrial interaction in the mechanism of acute reperfusion injury

Hans Michael Piper*, Yaser Abdallah, Sascha Kasseckert and Klaus-Dieter Schlüter

Institute of Physiology, Justus Liebig University, Aulweg 129, 35392 Giessen, Germany

* Corresponding author. Tel: +49 641 99 47 241; fax: +49 641 99 47 239. E-mail address: michael.piper{at}physiologie.med.uni-giessen.de

Currently, restoring blood flow in an acutely occluded vessel represents the most effective, long-term clinical therapy for acute myocardial infarction. Experimental research over the past years has demonstrated that the first minutes of reperfusion represent a window of opportunity for additional therapy that is yet unused in the clinical setting. Experimentally, it has been shown that a considerable part of myocardial injury developing after an episode of prolonged ischaemia and subsequent reperfusion is due to causes emerging during the period of reperfusion.1–6 This type of injury has been termed ‘reperfusion injury’. For a long time it had been difficult to prove the existence of this type of injury; this could only be done by identifying interventions applied just at the time of reperfusion that would reduce the otherwise resulting myocardial injury. Early studies in this area had shown that interventions during reperfusion aimed at controlling cytosolic [Ca2+] or the activation of the contractile machinery in cardiomyocytes could reduce cardiac cell necrosis.7–10 More recently, a protective protocol called ‘postconditioning’11 has been discovered that can be used in the clinical setting. In this protocol, very brief, repetitive bouts of ischaemia are deliberately applied during the first minutes of reperfusion. In ground-breaking work, Ovize and co-workers12,13 showed that postconditiong can reduce the signs of tissue injury, such as the release of myocardial enzymes, in patients receiving acute coronary revascularisation.

In a rapidly growing number of manuscripts, details of the protective signalling of postconditioning and pharmacological interventions designed to exploit its protective potential have been identified. It has become apparent that activation of specific protein kinases can provide and mediate cardiac protection during the reperfusion period. These have been termed ‘reperfusion injury salvage kinases’ (RISK).14–16 Not surprisingly, there are also protein kinases having adverse effects that can be termed ‘reperfusion injury-causing kinases’ (RICK). For protection to occur, RISK should be stimulated and RICK should be inhibited.

Two main cellular organelles have been identified as potential downstream targets of the protective signalling pathways in cardiomyocytes: the sarcoplasmic reticulum (SR) and the mitochondria. The question has also been raised whether the final, lethal effect of acute reperfusion injury on cardiomyocytes is one of necrosis or apopotosis. For the type of acute reperfusion injury where the intervention has to be applied during the first minutes of reperfusion, this question seems to have been answered: necrosis is predominant. The first indication of the mechanism responsible for this form of reperfusion-induced cell death came from histological studies showing that reperfused myocardium typically exhibits so-called ‘contraction bands’ within its contractile elements.8,17 These consist partially of extremely contracted myofibrils and partially of disrupted myofibrils (contraction band necrosis). We investigated whether reperfusion-induced contracture of cardiomyocytes is due to the normal mechanism of Ca2+- and energy-dependent cross-bridge activation (Ca2+-type contracture) or rather a rigor-dependent mechanism (rigor-type contracture) and found both mechanisms may be involved, depending on the specific circumstances of reperfusion.2,6,7,18

In this editorial, we propose a hypothesis on how and when the SR or mitochondria might be the target organelles of reperfusion protection by RISK activation or postconditioning and how this may relate to the type of contracture development that leads rapidly to cardiomyocyte necrosis.

The SR, as a player on the stage of early reperfusion, makes its appearance through rapid oscillatory Ca2+ movements that occur between the cytosol and the SR. The high cytosolic peak concentrations of Ca2+ in these oscillations trigger an uncontrolled activation of the myofibrils, which leads to the Ca2+-type contracture. Both Ca2+ uptake into the SR and myofibrillar activation require recovery of energy production by the mitochondria in the reperfused and re-oxygenated cell. This scenario (Figure 1) therefore occurs in reperfusion after ischaemia of a duration that is long enough to produce cytosolic Ca2+ overload but short enough to allow rapid metabolic recovery of mitochondrial energy production. We showed that the RISK pathway involving PI3K/Akt-eNOS-PKG or PKG alone interferes with SR-dependent Ca2+ movements because phospholamban-mediated SERCA activation enhances Ca2+ sequestration in the SR.10,19 Studies with agonists of natriuretic peptide agonists in animals and in the human confirm that activation of the PKG pathway at the time of reperfusion provides protection.20,21


Figure 1
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Scenario in which the SR dominates reperfusion injury (after moderate or slight ischaemia). Reperfusion provides ATP by oxidative phosphorylation (OxPhos) to SERCA and contractile elements. Ca2+ oscillates between cytosol and SR, released from the latter by the ryanodine receptor (RyR). High peak [Ca2+] and [ATP] cause Ca2+-type contracture.

 
The role of mitochondria as players on the stage of reperfusion injury has been identified by experiments targeting mitochondrial permeability transition pores (MPTP) in ischaemic-reperfused hearts. The opening of MPTP is favoured by various factors in reperfused cells, e.g. low [ATP], high [Ca2+], and reactive oxygen species,22 and this disables the affected mitochondria to produce ATP. Low [ATP] in reperfused myocardial cells promotes rigor-type contracture of the myofibrils.18,23 This scenario (Figure 2) requires longer or more severe ischaemic exposure than the one described above. It has been shown that the RISK pathway PI3K/Akt—GSK3β (glycogen synthase kinase 3β) interferes with this mitochondria-dependent mechanism of injury.14–16 GSK3β may be regarded as a RICK, since its inactivation through phosphorylation reduces the susceptibility of mitochondria for MPTP opening by a yet unidentified mechanism.


Figure 2
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Scenario in which the mitochondria dominate reperfusion injury (after severe ischaemia). Reperfusion initially causes repolarization of mitochondria ({Delta}{psi}), which promotes Ca2+ uptake through the uniporter (MCU). Subsequent MPTP opening prevents energy production. Low [ATP] causes rigor-type contracture.

 
SR and mitochondria may play their roles in separate acts, but they may also be on the stage together (Figure 3). This is because they can interact in the control of intracellular [Ca2+]. First, the SR-dependent oscillatory elevations of cytosolic [Ca2+] may cause a Ca2+ loading of the mitochondria and thus trigger MPTP opening. Indeed, we recently reported such an observation: in reperfused cardiomyocytes with SR-dependent Ca2+ oscillations, MPTP opening was reduced when either the mitochondrial Ca2+ uniporter or the ryanodine receptor was inhibited.24 Second, MPTP opening does not occur simultaneously in all mitochondria within a cell, and therefore an early MPTP opening in some mitochondria may increase the cytosolic Ca2+ overload (and thus SR-dependent Ca2+ oscillations by release of Ca2+ from these mitochondria) while the energy for the Ca2+-type contracture in the cell as a whole is still generated by the other, intact mitochondria. Observations of this kind have also been reported.25 Within the timeline of the alternatives described above, this scenario of SR-mitochondrial interaction would occur after ischaemic injury of medium severity.


Figure 3
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3 Scenario in which SR-mitochondrial interaction influences reperfusion injury (after medium ischaemia). Reperfusion provides ATP by oxidative phosphorylation (OxPhos) to SERCA and contractile elements. Ca2+ oscillates between cytosol and SR. High peak [Ca2+] and [ATP] cause Ca2+-type contracture and promote Ca2+ loading of part of the mitochondria. Subsequent MPTP opening in these mitochondria leads to Ca2+ release, which can augment the Ca2+ cycling between SR and cytosol.

 
Taking these considerations together, what can be concluded about the best myocardial protection? In the clinical setting, for a given patient with coronary occlusion awaiting revascularization, one cannot normally determine whether his/her myocardium is represented by the SR-dominated, the mitochondria-dominated, or the mixed scenario for reperfusion injury (or whether it is beyond any hope). What, then, would be a rational strategy to provide protection against acute reperfusion injury? First, it appears that postconditioning can activate the RISK pathways targeting both SR and mitochondria simultaneously, possibly by the common trunk of PI3K/Akt. Therefore, pharmacological activation of this common trunk of protective signalling seems promising. Second, interventions aimed at Ca2+ sequestration in the SR can be expected to protect during the early and mixed scenarios and during part of the mitochondria-dominated scenario, as the latter can be initiated by Ca2+ overload that drives MPTP opening. Third, interventions targeting MPTP opening can provide protection against the ultimate scenario of metabolic failure and rigor-type contracture, but they cannot be expected to protect against injury of the SR-dominated mechanism. To date, these strategies have not been tested and compared systematically in vivo, either experimentally or clinically, but the time is ripe to further investigate the importance of the roles played by the SR and mitochondria on the stage of reperfusion injury. It is, in particular, yet unclear how the various protective signalling pathways converge on the intracellular target organelles SR and mitochondria.

Conflict of interest: none declared.


   Notes
 
The opinions expressed in this article are not necessarily those of the European Society of Cardiology


   References
Top
 References
 

  1. Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res (1998) 38:291–300.[Free Full Text]
  2. Piper HM, Abdallah Y, Schafer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res (2004) 61:365–3671.[Abstract/Free Full Text]
  3. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med (2007) 357:1121–1135.[Free Full Text]
  4. Garcia-Dorado D, Vinten-Johansen J, Piper HM. Bringing preconditioning and postconditioning into focus. Cardiovasc Res (2006) 70:167–169.[Free Full Text]
  5. Rodriguez-Sinovas A, Abdallah Y, Piper HM, Garcia-Dorado D. Reperfusion injury as a therapeutic challenge in patients with acute myocardial infarction. Heart Fail Rev (2007) 12:207–216.[CrossRef][Web of Science][Medline]
  6. Piper HM, Kasseckert S, Abdallah Y. The sarcoplasmic reticulum as the primary target of reperfusion protection. Cardiovasc Res (2006) 70:170–173.[Free Full Text]
  7. Siegmund B, Klietz T, Schwartz P, Piper HM. Temporary contractile blockade prevents hypercontracture in anoxic-reoxygenated cardiomyocytes. Am J Physiol (1991) 260:H426–H435.[Web of Science][Medline]
  8. Garcia-Dorado D, Theroux P, Duran JM, Solares J, Alonso J, Sanz E, et al. Selective inhibition of the contractile apparatus: a new approach to modification of infarct size, infarct composition, and infarct geometry during coronary artery occlusion and reperfusion. Circulation (1992) 85:1160–1174.[Abstract/Free Full Text]
  9. Schäfer C, Ladilov Y, Inserte J, Schäfer M, Haffner S, Garcia-Dorado D, et al. Role of reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury. Cardiovasc Res (2001) 51:241–250.[Abstract/Free Full Text]
  10. Abdallah Y, Gkatzoflia A, Gligorievski D, Kasseckert S, Euler G, Schluter KD, et al. Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage. Cardiovasc Res (2006) 70:346–353.[Abstract/Free Full Text]
  11. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol (2003) 285:H579–H588.[Abstract/Free Full Text]
  12. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, et al. Postconditioning the human heart. Circulation (2005) 112:2143–2148.[Abstract/Free Full Text]
  13. Thibault H, Piot C, Ovize M. Postconditioning in man. Heart Fail Rev (2007) 12:245–248.[CrossRef][Web of Science][Medline]
  14. Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM. Postconditioning: a form of ‘modified reperfusion’ protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res (2004) 95:230–232.[Abstract/Free Full Text]
  15. Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res (2006) 69:178–185.[Abstract/Free Full Text]
  16. Gateau-Roesch O, Argaud L, Ovize M. Mitochondrial permeability transition pore and postconditioning. Cardiovasc Res (2006) 70:264–273.[Abstract/Free Full Text]
  17. Ganote CE. Contraction bands necrosis and irreversible myocardial injury. J Mol Cell Cardiol (1983) 15:67–73.[Web of Science][Medline]
  18. Ladilov Y, Efe O, Schäfer C, Rother B, Kasseckert S, Abdallah Y, et al. Reoxygenation-induced rigor-type contracture. J Mol Cell Cardiol (2003) 35:1481–1490.[CrossRef][Web of Science][Medline]
  19. Abdallah Y, Gkatzoflia A, Pieper H, Zoga E, Walther S, Kasseckert S, et al. Mechanism of cGMP-mediated protection in a cellular model of myocardial reperfusion injury. Cardiovasc Res (2005) 66:123–131.[Abstract/Free Full Text]
  20. Padilla F, Garcia-Dorado D, Agulló L, Barrabés JA, Inserte J, Escalona N, et al. Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs. Cardiovasc Res (2001) 51:592–600.[Abstract/Free Full Text]
  21. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet (2007) 370:1483–1493.[CrossRef][Web of Science][Medline]
  22. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res (2004) 61:372–385.[Abstract/Free Full Text]
  23. Ventura-Clapier R, Veksler V. Myocardial ischemic contracture. Metabolites affect rigor tension development and stiffness. Circ Res (1994) 74:920–929.[Abstract/Free Full Text]
  24. Abdallah Y, Said M, Heger J, Gligorievski D, Kasseckert SA, Schaefer C, et al. SR-induced mitochondrial permeability transition triggers reperfusion-induced hypercontracture of cardiac myocytes. Eur Heart J (2007) 28(Suppl.):361. (Abstract).
  25. Ruiz-Meana M, Abellan A, Miro-Casas E, Garcia-Dorado D. Opening of mitochondrial permeability transition pore induces hypercontracture in Ca(2+) overloaded cardiac myocytes. Basic Res Cardiol (2007) 102:542–552.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CirculationHome page
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]

Home page
 Cardiovasc ResHome page
D. Garcia-Dorado, H. M. Piper, and D. A. Eisner
Sarcoplasmic reticulum and mitochondria in cardiac pathophysiology
Cardiovasc Res, January 15, 2008; 77(2): 231 - 233.
[Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
77/2/234    most recent
cvm066v3
cvm066v2
cvm066v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Piper, H. M.
Right arrow Articles by Schlüter, K.-D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Piper, H. M.
Right arrow Articles by Schlüter, K.-D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?