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Cardiovascular Research 2006 70(2):264-273; doi:10.1016/j.cardiores.2006.02.024
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Copyright © 2006, European Society of Cardiology

Mitochondrial permeability transition pore and postconditioning

Odile Gateau-Roesch, Laurent Argaud and Michel Ovize*

INSERM E 0226, Université Claude Bernard Lyon I, 8 Avenue Rockefeller, 69373 Lyon cedex 08, France
Hôpital Louis Pradel, Hospices Civils de Lyon, 69437 Lyon cedex 03, France

* Corresponding author. Inserm E0226-Laboratoire de Physiologie Lyon-Nord, 8, avenue Rockefeller, 69373 Lyon, France. Tel.: +33 4 78 77 70 74; fax: +33 4 78 77 71 75. Email address: ovize{at}sante.univ-lyon1.fr

Received 31 August 2005; revised 10 February 2006; accepted 21 February 2006


   Abstract
Top
 Abstract
1. Why would mPTP...
 2. Evidence for mPTP...
 3. Limitations
 4. Clinical perspectives
 References
 
Postconditioning has recently been described as a powerful cardioprotection that prevents lethal reperfusion injury. Growing evidence suggests that mitochondrial permeability transition may be a key event in postconditioning. This proposition arises from the complementary observations that: (1) conditions for the mitochondrial permeability transition pore (mPTP) opening are built up during early reperfusion, (2) mPTP opens at the time of reperfusion, (3) transgenic structural alteration of mPTP modifies its opening probability following ischemia–reperfusion, (4) mPTP plays a role in preconditioning, and (5) postconditioning attenuates lethal reperfusion injury. We review in this article current evidence for an important role of the mitochondrial transition pore in postconditioning.

KEYWORDS Ischemia; Reperfusion; Mitochondria

The development of thrombolysis and coronary angioplasty has clearly improved the prognosis of patients with acute myocardial infarction (AMI). Numerous studies have demonstrated that reperfusion can limit infarct size and improve functional recovery [1–3]. Despite these beneficial effects, reperfusion has been termed "a double-edged sword" since it may also have detrimental consequences, including myocardial stunning, ventricular arrhythmias, and no-reflow that may partly attenuate its beneficial effects [4–9].

Besides these functional alterations, it has been proposed that reperfusion may actually irreversibly damage the previously ischemic myocardium. There has been much debate as to whether reperfusion would simply accelerate cell death or truly kill cardiomyocytes that would otherwise have survived (in the absence of the noxious effects of reperfusion). Demonstration of the existence of lethal reperfusion injury requires that a given intervention, performed at the time of reflow, does limit infarct size. Although several investigations during the past decades reported that pharmacological interventions at reperfusion may attenuate cardiomyocyte cell death, the concept of lethal reperfusion injury faced some skepticism mainly due to contradictory results, inconsistent data and failure to reproduce these data in in vivo models and in all animal species [10,11].

The description of postconditioning by Vinten-Johansen's group established the existence and importance of lethal reperfusion injury [12]. These authors first reported that brief episodes of ischemia performed just at the onset of reperfusion following a prolonged ischemic insult dramatically reduced infarct size. This observation has now been reproduced in several experimental preparations and animal species [13–16]. Lethal reperfusion has been reported to include both necrosis and apoptosis [17,18].

A mechanistic understanding of postconditioning can be gained by an analogy to preconditioning. Among other potential key players of postconditioning, the mitochondrial permeability transition pore (mPTP) has recently received much attention. This article will focus on our current knowledge of the role of mitochondrial permeability transition in postconditioning.


   1. Why would mPTP opening be a key event of postconditioning?
Top
 Abstract
 1. Why would mPTP...
2. Evidence for mPTP...
 3. Limitations
 4. Clinical perspectives
 References
 
1.1 Biology of lethal reperfusion injury
Lethal reperfusion injury of the myocardium is a complex phenomenon that encompasses several etiologies. A description of the natural history of postconditioning indicates that most of the detrimental effects of reperfusion are triggered within the first minutes following the re-opening of the occluded coronary artery [12,15].

Briefly, the increase in anaerobic glycolysis during ischemia results in progressive accumulation of protons and lactic acid, eventually inhibiting glycolytic flux and synthesis of ATP [19–21]. As the cardiomyocyte attempts to correct acidosis via the Na+/H+ exchanger, it will consequently load with Na+, which cannot be extruded from the cytosol since the Na+/K+-ATPase is failing due to the lack of ATP. Secondary activation of the Na+/Ca2+ exchanger, in its reverse mode, will help pump Na+ out of the cell, but favor cytosolic accumulation of Ca2+. Prolonged ischemia induces progressive failure of the ionic homeostasis which ultimately causes accumulation of intracellular Na+ and Ca2+, ATP decline, and development of ischemic contracture.

Reperfusion–reoxygenation will rescue a majority of jeopardized cardiomyocytes. However, many factors may cooperate to provoke lethal reperfusion injury. In the first minutes of reperfusion, rapid correction of acidosis via the Na+/H+ exchanger will cause secondary activation of the Na+/Ca2+ exchanger in the reverse mode and aggravate cytosolic Ca2+ accumulation. Abrupt re-exposure of the ischemia-inhibited respiratory chain to oxygen will generate a membrane potential to drive ATP synthesis, but then lead to rapid matrix Ca2+ overload and massive production of oxygen-derived free radicals.

1.2 Transition pore opening at reperfusion
Under normal physiological conditions, the mitochondrial inner membrane is impermeable to almost all metabolites and ions, and the mPTP is in a closed conformation. Under some stress conditions, the mPTP may open and allow the equilibration of molecules smaller than approximately 1500 Da [22–27]. Osmotic force of matrix proteins results in matrix swelling, leading to further rupture of the outer membrane and release in the cytosol of proapoptotic factors like cytochrome c. In addition, disruption of the mitochondrial membrane potential also results in the ATP synthase to behave as an ATPase and accelerate energy depletion secondary to the ischemic insult.

What is the mechanism of mPTP activation by the abovementioned ionic and metabolic alterations of reperfusion? Indeed, the components of lethal reperfusion injury correspond to the known modulators of mPTP opening [28–30]. Opening of the mPTP is favoured by decreased inner membrane potential, low adenine nucleotides, matrix Ca2+ accumulation, oxidative stress and alkalinization, and inhibited by matrix cations like Mg2+, Mn2+, Sr2+. As mentioned earlier, ischemia–reperfusion combines several conditions that can trigger mPTP opening, including matrix Ca2+ overload, overproduction of reactive oxygen species, depletion of adenine nucleotides and accumulation of inorganic phosphates. In isolated cardiomyocyte preparations, it has been demonstrated using fluorescence microscopy that permeability transition occurs after oxidative stress or re-oxygenation [31,32]. Akao et al. reported that cultured cardiomyocytes exposed to H2O2 undergo a rapid drop in inner membrane potential that is mediated by opening of the mPTP, as evidenced by the concomitant release of the fluorescent dye calcein entrapped into the matrix [32].

In the isolated heart model, Di Lisa et al. demonstrated that the cytosolic release of NAD+, presented as a surrogate marker of mPTP opening, occurs at the time of reperfusion following a prolonged ischemic insult [33]. Griffiths et al. used the [3H]2-deoxyglucose ([3H]2-DG) entrapment technique to investigate the kinetics of in situ mPTP opening [34]. Briefly, after entering cardiomyocytes via the glucose transporter, [3H]2-DG is metabolized to 2-deoxyglucose-6-phosphate, and remains entrapped into the cytosol. It does not enter the mitochondria unless the mPTP opens, whereupon it equilibrates rapidly between the cytosol and mitochondrial matrix compartments. The extent to which [3H]2-DG is entrapped within mitochondria has been used as an indicator of the proportion of mitochondria that have undergone the mPTP. This technique was employed by Halestrap's group to demonstrate that mPTP opening does not happen during ischemia, but occurs within the first five minutes of reflow following a 30 min ischemia in the isolated rat heart [34]. Importantly, the time course of mPTP opening appeared to match the rapid correction of pH that occurs at reperfusion (Fig. 1).


Figure 1
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  		Fig. 1 mPTP opens at reperfusion Opening of mPTP was assessed using the [3H]2-deoxyglucose entrapment technique. Isolated rat hearts underwent 30 min of global ischemia and 30 min of reperfusion. Transition pore opening occurred within the first 5 min of reflow, following rapid recovery of pH (from Ref. [34], with permission).

 
1.3 Structural alteration of mPTP modifies its open probability following ischemia–reperfusion
Additional evidence for a major role of the mPTP in lethal reperfusion injury recently came from the use of transgenic mice lacking cyclophilin D (cypD). CypD is a mitochondrial member of the family of peptidyl-prolyl cis–trans isomerases (PPIases). In the presence of high matrix Ca2+ concentration, cypD has been reported to modify the conformation of the ANT, so that it no longer functions as a nucleotide transporter, but rather as a channel component for the mPTP [35,36]. CsA is considered to inhibit mPTP opening by preventing the binding of cypD to the ANT [35]. The liver mitochondria of cypD-deficient mice, where the Ppif gene encoding for mitochondrial cypD had been inactivated, display a desensitization of the mPTP to Ca2+, yet their mPTP response to depolarization, pH, adenine nucleotides and thiol oxidants appears unchanged [37]. In vitro, CypD-deficient cells showed an increased resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload [38]. In vivo, cypD-deficient mice developed smaller infarcts following 30 min of coronary artery occlusion followed by 2 h of reperfusion (38). Similarly, Baines et al. reported that the CypD-deficient Ppif– / – mice developed significantly smaller infarcts than wild-type Ppif+/+ following 60 min of ischemia and 24 h of reperfusion [39]. Mitochondria isolated from the hearts of Ppif– / – mice were resistant to mitochondrial swelling and permeability transition in vitro [39]. These results strongly support the proposal that mPTP opening, triggered by mitochondrial Ca2+ overload and overproduction of reactive oxygen species, plays a central role in lethal reperfusion injury [40]. The structure of the mPTP remains a matter of debate, however. Kokoszka et al. reported that liver mitochondria from ANT-deficient mice can still undergo CsA-inhibitable permeability transition, suggesting that the ADP/ATP translocator may not be an essential structural component of the mPTP [41]. In the absence of structural characterization, permeability transition should be considered as a function and the genetic and functional approaches must be combined for a comprehensive understanding of the role of the mPTP in cardioprotection.

1.4 Lessons from preconditioning
The experimental design of postconditioning mirrors preconditioning and the cardioprotection that is provided by these phenomena is similar. Thus, the mechanisms of pre- and postconditioning are presumably similar. As a matter of fact, several important elements of signaling pathways, including adenosine receptors, PI3-kinase, eNOS, are involved in both preconditioning and postconditioning [42–45].

Several studies have demonstrated a role for the mPTP in preconditioning. Yellon's group demonstrated that the mPTP inhibitor cyclosporin A (CsA) limits infarct size to a similar extent than ischemic preconditioning in the isolated rat heart preparation [46,47]. Paradoxically, these authors also reported that CsA prevented preconditioning when given before the triggering stimulus, suggesting that transient opening of the mPTP may be involved in the induction of the protection [48]. Using the [3H]2-deoxyglucose entrapment technique in a similar experimental preparation, Javadov et al. reported that preconditioning inhibits mPTP opening during early reperfusion [49]. Argaud et al. reported that mitochondria isolated from in vivo preconditioned rabbit hearts display a delayed mPTP opening when exposed to a Ca2+ overload [50]. This effect was closely mimicked by CsA, as well as by another mPTP inhibitor NIM811 [50]. Because CsA has been able to protect the heart also when given at reperfusion, it is tempting to hypothesize that mPTP would be involved in postconditioning as well as it seemed involved in preconditioning.

1.5 Postconditioning (including "controlled reperfusion") attenuates lethal reperfusion injury
Repetition of brief episodes of ischemia–reperfusion within one minute of reflow following a prolonged ischemic insult significantly reduces infarct size in the dog, rabbit and rat hearts [12–16,51,52]. One study by Schwartz et al. reported that three episodes of 30 s of ischemia and 30 s of reperfusion could not protect the pig heart [53]. Noteworthy, these authors reported that this algorithm of brief episodes of ischemia–reperfusion was able to activate ERK and Akt, but did not allow infarct size reduction, suggesting that this signalling pathway is not involved in postconditioning [53]. In a similar model, however, others were able to postcondition the pig heart [54]. Sun et al. reported that postconditioning attenuates rat hepatocyte apoptosis in rat liver submitted to prolonged ischemia–reperfusion [55]. These well-designed, controlled, studies performed in independent laboratories, using various experimental preparations support the existence of postconditioning as well as the existence of lethal reperfusion injury.

Besides limiting the final effect of reperfusion injury, postconditioning altered its components. Vinten-Johanssen's group reported that the antinecrotic effect of postconditioning is associated with beneficial anti-inflammatory and antioxidant effects. Zhao et al. demonstrated in the dog model that postconditioning limits tissue oedema within the myocardial area at risk, attenuates polymorphonuclear accumulation, and protects endothelial function [12]. Sun et al. reported in primary cultured neonatal cardiomyocytes that postconditioning reduces reactive oxygen species generation and subsequent lipid peroxidation and attenuates intracellular and mitochondrial calcium concentrations [56]. It has been long known that modulation of the conditions of reperfusion, i.e. "controlled reperfusion," can protect the ischemic heart [57–60]. Bopassa et al. recently demonstrated that the protection afforded by low-pressure reperfusion closely resembles that of postconditioning in the isolated rat heart, and that "controlled reperfusion" may be considered as a form of postconditioning [14,61].


   2. Evidence for mPTP opening as a major player of postconditioning
Top
 Abstract
 1. Why would mPTP...
 2. Evidence for mPTP...
3. Limitations
 4. Clinical perspectives
 References
 
Evidence for a role of mPTP in postconditioning was provided by the recent study of Argaud et al. [62]. In that study, anesthetized rabbits underwent 30 min of ischemia and 4 or 72 h of reperfusion. Preconditioning (one episode of 5 min ischemia–5 min reperfusion), postconditioning (four episodes of 1 min ischemia–1 min reperfusion, starting one minute after reflow) and the specific mPTP inhibitor NIM811 (given at the time of reperfusion) limited infarct size to a similar extent (Fig. 2).


Figure 2
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  		Fig. 2 Postconditioning and mPTP inhibition at reperfusion by NIM811 reduce infarct size. Both Postconditioning and the specific mPTP inhibitor NIM811, administrated at the time of reperfusion, reduced infarct size in the rabbit heart. All data points for these two groups, as well as for preconditioned hearts, lie below the control regression line, indicating that for any size of the area at risk, postconditioned or NIM811-treated hearts developed significantly smaller infarcts than controls (adapted from Refs. [62], with permission). AR: area at risk; AN: area of necrosis (in grams).

 
Based on previous work by Ichas et al., Argaud et al. had set up a model to quantitate mPTP opening triggered by a Ca2+ overload [50,63]. In this model, hearts are pre- or postconditioned in vivo, and then mitochondria are isolated from the respective areas at risk to test mPTP opening in vitro. Following the thorough isolation procedure, mitochondria are exposed to a repetitive administration of CaCl2. This repetitive mode was designed to quantitate the amount of Ca2+ required to open the mPTP and differentiate pre-treated from control mitochondria. As depicted in Fig. 3, the abrupt increase in extra-mitochondrial Ca2+ concentration corresponds to mPTP opening, since it is blocked by CsA or NIM811, and because mitochondria analyzed by electron microscopy after this abrupt increase in Ca2+ concentration exhibit swelling, ruptured membranes, altered cristae compatible with permeability transition (Fig. 4). Argaud et al. reported that mitochondria prepared from preconditioned hearts, or from hearts that had been pre-treated by CsA, displayed an enhanced resistance to Ca2+ overload [50]. One might question whether this delayed Ca2+-induced mPTP opening might be a consequence rather than a cause of the improved myocardial viability observed in pre- or postconditioned reperfused hearts. In other words, following the prolonged ischemia–reperfusion, the isolation procedure could select more resistant subpopulations of mitochondria in pre- or postconditioned hearts than in control hearts. We addressed this issue by comparing mitochondria isolated from preconditioned and control hearts after a brief, fully reversible (i.e. without any necrosis) 10 min ischemia [50]. We found that the difference between control and preconditioned hearts persisted whatever the duration of ischemia and reperfusion. This demonstrates that a modification of Ca2+-induced mPTP opening is not a consequence of reduced cardiomyocyte death, but rather suggests that it may be a cause.


Figure 3
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  		Fig. 3 Ca2+-induced mPTP opening in preconditioned and postconditioned hearts. The Ca2+ overload required to open the mPTP pore of mitochondria isolated from pre- or postconditioned rabbit hearts was significantly higher than that used for controls (from Ref. [62], with permission).

 

Figure 4
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  		Fig. 4 Isolated mitochondria before and after Ca2+-induced mPTP opening. Electron microscopy confirmed the integrity and purify of isolated mitochondria before Ca2+-induced MPT pore opening (A). Following Ca2+-induced MPT pore opening, mitochondria appeared swollen with disappearance of membrane integrity (B) (from Ref. [50], with permission).

 
What happens in postconditioned hearts? Mitochondria isolated from the risk region of control hearts exhibited reduced resistance to Ca2+ overload in vitro, and accelerated mPTP opening when compared to sham (Fig. 3). In contrast, mitochondria isolated from postconditioned hearts displayed an enhanced resistance of the mPTP to Ca2+ overload. This pattern of inhibition of mPTP opening by postconditioning was very similar to that observed in hearts treated with the mPTP inhibitor NIM811 at the onset of reperfusion, as well as that of preconditioned rabbits [50,62,64]. Electron microscopic examination of myocardium obtained from sham animals shows mitochondria with dense cristae and intact outer membranes (Fig. 5). Mitochondria from control hearts, that underwent 30 min of ischemia and 60 min of reperfusion, display damaged cristae and disrupted mitochondrial membranes. In contrast, the morphology of mitochondria from area at risk of postconditioned and preconditioned hearts was better preserved (Fig. 5). Using a similar approach, Bopassa et al. reported that reperfusing isolated rat hearts with a low pressure (70 cm H2O versus 100 cm H2O in controls) limited infarct to a similar extent than postconditioning [14]. Here again, mitochondria isolated from hearts reperfused with low pressure displayed an increased resistance of mPTP opening following in vitro Ca2+ overload [14]. These two studies support a key role for the mPTP pore in postconditioning.


Figure 5
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  		Fig. 5 Electron microscopic examination of postconditioned hearts. Electron microscopic examination of heart from sham animal shows homogenous population of mitochondria with dense cristae and intact outer membranes. Control hearts exhibit many swollen mitochondria with damaged cristae. Many mitochondria in preconditioned (Prec.) and postconditioned (Postc.) hearts have near normal morphology with intact membranes and dense matrix.

 
Involvement of the mPTP is further supported by evidence that pharmacological inhibition of the mPTP at the time of reflow protects the heart to a similar extent than postconditioning. Hausenloy et al. and others reported that CsA or sanghliferin A (another inhibitor of the mPTP), given at the time of reperfusion, can limit infarct size in the isolated rat heart [46]. Unfortunately, the commonly used CsA is not specific for cyclophilin D. CsA also binds to the cytosolic cyclophilin A, and thereby interferes with several molecular targets within the cellular survival/death pathways, including HSP70, HSP90, ERK, p38MAPK, and Akt [65–67]. Argaud et al. demonstrated that the specific mPTP inhibitor NIM811, a cyclosporin derivative devoid of activity on calcineurin, both increased the resistance of mPTP to Ca2+ overload and limited infarct size when given at the time of reflow [62,64].

Further indirect evidence for a role of mPTP in postconditioning comes from the demonstration that mPTP opening is downstream the RISK pathway in postconditioned hearts. Involvement of the RISK pathway in postconditioning has been suggested by Tsang et al. and Yang et al. who reported that pharmacological inhibition of PI3K and ME1/2-ERK pathways could prevent postconditioning [13,16]. Additional linkage between the RISK pathway and the mPTP was recently demonstrated by Bopassa et al. [68]. In that study, both ischemic postconditioning and low-pressure reperfusion resulted in a significant reduction in infarct size. Both ischemic postconditioning and low-pressure reperfusion activated phosphorylation of Akt, and increased the resistance of the mitochondrial transition pore to Ca2+ overload (Fig. 6). Inhibition of Akt by either wortmannin or the more specific LY294002 in postconditioned and low-pressure hearts prevented Akt phosphorylation, abolished the enhanced resistance of the mPTP to Ca2+ overload and prevented infarct size reduction. These data support the proposal that mPTP opening is regulated by the PI3K-Akt pathway in postconditioning.


Figure 6
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  		Fig. 6 Inhibition of PI3K prevents inhibition of mPTP opening (panel A) and infarct size reduction (panel B) by Postconditioning. Panel A: the increased resistance of the mPTP to Ca2+ overload in Postconditioned and low-pressure (LP) hearts was prevented by blockade of PI3-kinase. Panel B: inhibition of PI3-kinase by either wortmannin (WT) or LY294002 (LY) prevented troponin I release reduction by Postconditioning or low-pressure reperfusion in isolated rat hearts (from Ref. [68], with permission).

 
How the mPTP is linked to the RISK pathway remains unknown. One may speculate that several players, downstream of PI3K-Akt, may be involved in mPTP inhibition by postconditioning. Such an inhibition might result from direct action on the mPTP, as might be the case for Bcl2, or from modifications of the conditions favoring mPTP opening, as would be the case for example for mitochondrial K+ATP channels or the respiratory chain. Serviddio et al. demonstrated that hypoxic postconditioning limits peroxide production by mitochondria [69]. Activators of mitochondrial K+ATP channels protect the ischemic heart when given at the onset of reperfusion and are known to inhibit mPTP opening [70–72]. Juhaszova et al. recently proposed that GSK3β may prevent mPTP opening in preconditioning [73]. Whether GSK3β might also be a good candidate to link the RISK pathway to mPTP inhibition in postconditioned hearts is yet currently unknown. GSK3β, which is highly active in unstimulated cells, contributes to many important cellular processes including metabolism, transcription or cell division. Tong et al. and Gross et al. reported that preconditioning inhibits GSK3β activity and that selective pharmacological inhibition of GSK3β is cardioprotective in the rat heart [74,75]. Negative upstream regulators of GSK3β include PI3K, PKC, TOR (target of rapamycin) and MAPKs (mitogen activated protein kinases). The mPTP may be a downstream target of GSK3β. Using adult rat cardiomyocytes or cultured neonatal rat cardiomyocytes, Juhaszova et al. demonstrated that hypoxia–reoxygenation significantly reduces mPTP opening following a stress by reactive oxygen species (ROS) [73]. In cardiomyocytes from transgenic mice expressing a non-inhibitable isoform of GSK3β, hypoxic and pharmacological preconditioning was inefficient, and mPTP opening secondary to ROS exposition was not inhibited. Further studies are needed to determine whether GSK3β is a good candidate to link the RISK pathway to the mPTP in postconditioning.


   3. Limitations
Top
 Abstract
 1. Why would mPTP...
 2. Evidence for mPTP...
 3. Limitations
4. Clinical perspectives
 References
 
Despite growing evidence for a role of the mPTP in postconditioning (and preconditioning), the demonstration remains indirect and establishment of a causal relationship between mPTP inhibition and postconditioning is currently not feasible. This is due to several limitations.

First, the molecular structure of the mega-channel is still debated. It is likely that a more precise characterization will help understand its function(s) in cell physiology and pathophysiology, including ischemia–reperfusion.

Second, the pharmacological tools used to investigate its role in various conditions are troublesome. The classical cyclosporin A, a powerful inhibitor of mPTP opening is nonspecific as mentioned earlier. Although its use allowed major progress in the understanding of mitochondrial permeability transition, caution is required when interpreting data in experimental conditions (like ischemia–reperfusion) that may involve other potential molecular targets of CsA. More specific inhibitors of mPTP, like some derivatives of CsA, are recommended. Openers of the mPTP, including atractyloside, have been used in experimental models to prevent preconditioning. Unfortunately, binding of atractyloside to ANT has two consequences: it does open the mPTP, but it also inhibits ADP transport into the mitochondria, prevents its mitochondrial phosphorylation, and blocks oxidative phosphorylation. In other words, blocking of preconditioning by atractyloside may not be specifically related to mPTP opening, but may at least in part be due to a detrimental effect on energy production that is of major importance in cell survival under hypoxia and reoxygenation conditions.

Third, the study of mitochondrial permeability transition requires the thorough use and cautious interpretation of various techniques (described elsewhere), including for example isolation of mitochondria, fluorescence probing, measurement of the cytosolic release of NAD+, or assessment of [3H]2-deoxyglucose tissue mitochondrial entrapment, that are each applied in very particular experimental preparations ranging from isolated mitochondria to in vivo heart.


   4. Clinical perspectives
Top
 Abstract
 1. Why would mPTP...
 2. Evidence for mPTP...
 3. Limitations
 4. Clinical perspectives
References
 
Clearly the potential clinical implications of postconditioning are major. Obvious questions are whether it can protect the human heart, and whether one should perform postconditioning in clinical practice as it is performed in animal preparations (e.g. by re-inflating the angioplasty balloon several times to reproduce brief episodes of ischemia) or whether we should focus on the molecular mechanism of postconditioning in order to develop new pharmacological agents aimed at protecting the human heart during AMI.

Our group recently demonstrated that one can postcondition the human heart by coronary angioplasty in patients with ongoing acute myocardial infarction [76]. Staat et al. reported that four episodes of one minute inflation–deflation of the angioplasty balloon performed within one minute of reflow in patients with an acutely occluded coronary artery can reduce creatine kinase release (a surrogate marker of infarct size) over the first 72 h of reperfusion by 36%. Whether all patients would benefit from postconditioning remains to be determined: age, co-morbidities (diabetes, hyperlipidemia,), duration of ischemia, time of intervention after reperfusion, may be confounding factors. Tang et al. recently reported that postconditioning is ineffective when the prolonged ischemic insult is extended over 45 min in the conscious rat model [77]. Unfortunately, a minority of patients with ongoing AMI can benefit from coronary angioplasty. In contrast, a larger number of AMI patients receive a thrombolytic treatment. One may thus expect that a pharmacological agent targeting a key component of the postconditioning signaling pathway, possibly the mitochondrial permeability transition pore, may prove an efficient adjunct to reperfusion in the future.


   Notes
 
Time for primary review 26 days


   References
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 Abstract
 1. Why would mPTP...
 2. Evidence for mPTP...
 3. Limitations
 4. Clinical perspectives
 References
 

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