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Cardiovascular Research 2002 55(3):456-465; doi:10.1016/S0008-6363(02)00441-8
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Copyright © 2002, European Society of Cardiology

Gap junction-mediated intercellular communication in ischemic preconditioning

David Garcia-Dorado*, Marisol Ruiz-Meana, Ferran Padilla, Antonio Rodriguez-Sinovas and Maribel Mirabet

Servicio de Cardiología, Hospital Vall d’Hebron, Passeig Vall d’Hebron 119–129, 08035 Barcelona, Spain

dgdorado{at}hg.vhebron.es

* Corresponding author. Tel.: +34-93-489-4038; fax: +34-93-489-4032

Received 26 November 2001; accepted 8 April 2002


   Abstract
Top
 Abstract
1. Gap junctions in...
 2. The mechanism of...
 3. Gap junction communication...
 4. Delayed cell death...
 5. Conclusion
 References
 
Gap junction-mediated communication can modulate cell death in different tissues. In myocardium, gap junction communication is altered during ischemia, which contributes to the development of arrhythmias, but still allows synchronization of the onset of rigor contracture in the progression of injury. During reperfusion, gap junction communication allows cell-to-cell spread of hypercontracture and cell death. Since the intracellular signal transduction systems involved in modulation of gap junction-mediated communication are activated during ischemic preconditioning, the hypothesis can be raised that gap junctions are end-effectors of preconditioning contributing to its protective effect on cell death. This paper reviews the available information supporting this hypothesis. It has been shown that ischemic preconditioning may influence gap junction-mediated intercellular communication by activation of different kinases, including PKC and MAPK cascades, and by preservation of cGMP among other mechanisms. Connexin phosphorylation by PKC, p38/MAPK, and PKG, tends to reduce intercellular communication. This effect of ischemic preconditioning seems to have no relevant consequences during prolonged ischemia, and does not significantly modify the time course of either electrical uncoupling or the frequency or temporal distribution of ventricular arrhythmias during this period. However, any modification of gap junction communication during initial reperfusion could contribute to the reduced extent of hypercontracture and cell death observed in preconditioned hearts. The potential role of gap junctions as effectors of ischemic preconditioning against lethal injury secondary to ischemia–reperfusion deserves to be investigated in depth.

KEYWORDS Ischemia; Reperfusion; Myocytes; Infarction; Gap junctions; Preconditioning

The mechanism by which ischemic preconditioning protects myocardium against cell death secondary to ischemia–reperfusion is not known. Gap junctions have been recently shown to be implicated in the spreading of necrotic cell death secondary to ischemia–reperfusion in myocardium and other tissues. The purpose of this article is to analyze whether the existing evidence allows us to propose the hypothesis that the protective effect of ischemic preconditioning against lethal injury secondary to ischemia–reperfusion can at least be partially explained as a consequence of its effect on gap junction-mediated intercellular communication. The review will be focused on ‘classical’ preconditioning. Neither the potential role of gap junctions in the mechanism of the delayed or second window protection against lethal injury [1,2] nor the late effects of preconditioning on gap junction communication derived from its effect on infarct size and ventricular remodeling will be reviewed here.


   1. Gap junctions in the heart
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 Abstract
 1. Gap junctions in...
2. The mechanism of...
 3. Gap junction communication...
 4. Delayed cell death...
 5. Conclusion
 References
 
Cardiac myocytes are tightly interconnected by means of highly specialized regions of the plasma membrane called gap junctions. Intercellular communication through gap junctions allows myocardium to behave like a functional syncytium [3,4]. The structure and properties of cardiac gap junctions have been reviewed in detail elsewhere [3–6]. Gap junctions are composed of clusters of transmembrane channels connecting the cytosol of adjacent cells in areas in which the membranes of the two cells are in juxtaposition. Each channel is the result of the docking of two hemichannels from each of the two adjacent cells. There are many types of connexins, identified by a number reflecting their molecular weight, but Cx43 is by far the most abundant connexin present in myocardial tissue [7,8]. In adult cardiomyocytes, gap junctions are located almost exclusively in intercalated disks.

It has been demonstrated that the alteration of gap junction-mediated communication modifies passive electrical properties and propagation of action potential, leading to electrical instability and arrhythmias in acutely ischemic myocardium [9], as well as in chronically hibernated or infarcted myocardium [10,11]. However, although it is well known that gap junctions allow the exchange of small molecules and ions [3,6,12], their role in metabolic coupling between adult cardiac myocytes is poorly understood. They have recently been involved in the pathophysiology of post-reperfusion myocardial necrosis [13,14]. The permeability of gap junction channels can be modified by at least two different mechanisms, probably including torsion with rotation of the two channel ends in opposite directions [4], which narrows or closes the channel lumen, and a ball and chain mechanism [15,16]. The regulation of these mechanisms includes multiple intercellular signaling systems so far not completely understood [3,17–28]. Many of these signaling systems modify the gating properties of GJ by inducing changes in the phosphorylation status of Cx43 [3,17–19,21,23,24,29]. In addition, mechanisms of regulation of gap junction communication apart from modification in their gating properties seem also to be regulated by changes in the phosphorylation status of different proteins. These mechanisms control the expression and turnover of CX43, its assembly into hemichannels, the intracellular trafficking towards the sarcolemma, and docking with hemichannels from adjacent cells [3,4,30,31]. Changes in expression and turnover are probably of less importance during early reperfusion, but could be prominent thereafter.


   2. The mechanism of the protection afforded by ischemic preconditioning
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 Abstract
 1. Gap junctions in...
 2. The mechanism of...
3. Gap junction communication...
 4. Delayed cell death...
 5. Conclusion
 References
 
2.1 Ischemic preconditioning against lethal injury secondary to ischemia–reperfusion
Ischemic preconditioning is a transient status of increased tolerance to ischemia–reperfusion induced by one or various episodes of brief ischemia. While its protective effects against arrhythmias and post-ischemic contractile failure (stunning) are largely debated [32], the originally described protection cell death as determined by measurement of infarct size [33] has been unambiguously demonstrated to occur in investigated species, and this article will focus on this aspect.

2.2 The effector mechanism of ischemic preconditioning: unknown
Since its initial description, a huge research effort has resulted in an extensive although incomplete knowledge of the mechanisms responsible for the induction of the enhanced tolerance of preconditioned myocardium to transient ischemia. A series of membrane receptors that are potentially involved in the triggering of the preconditioned signal transduction cascades, and some potential interrelations between them have been described [1,32,34–37]. Mitochondria, in particular their ATP-dependent K+ channels, have also been implicated in the genesis of the protective effect [32,35,36,38,39]. However, there is an almost complete lack of information on the nature of the links connecting these initial events in the genesis of preconditioning with the prevention of cardiomyocyte cell death following ischemia–reperfusion. The identification of the end-effectors of ischemic preconditioning requires in the first place an adequate understanding of the ultimate mechanisms of cell death during ischemia–reperfusion. These have been reviewed elsewhere [40], and will be briefly discussed in the following section.

2.3 The mechanism of protection: reduced injury at the time of reperfusion
A prominent and often neglected characteristic of the protection afforded by ischemic preconditioning is that its protective effect can only be observed, with very few exceptions, after reperfusion [41]. The slight modifications induced by preconditioning in the time course of functional, metabolic, or ionic changes occurring in the ischemic myocardium can hardly explain the protection observed at the time of reperfusion. The most prominent of these modifications, a reduction in the rate of fall of intracellular pH, seems largely independent of the protective effect. In fact, acidosis delays ATP depletion during ischemia [42], prevents hypercontracture during reperfusion [43], and inhibits the opening of the mitochondrial transition pore [44], and its attenuation should accelerate the progression of ischemic injury [43]. The rate of ATP depletion during sustained ischemia has been found to be slightly slowed in some models of preconditioned myocardium [41,42,45–47], but not in others in which preconditioning is equally protective [48,49]. The onset of rigor contracture may be slightly delayed or hastened by preconditioning depending on the models [50,51]. This is particularly interesting, since rigor onset represents a milestone in the progression of ischemic injury that marks the beginning of cytosolic Ca2+ rise [52,53]. Although the interval between the initiation of oxygen deprivation and the onset of rigor varies largely depending on the conditions, the interval after rigor development during which reoxygenation can be performed without inducing hypercontracture varies much less [53]. PKC stimulation, which effectively mimics the protective effect of preconditioning in isolated cardiomyocytes, does not modify rigor onset or the magnitude–time course of cytosolic Ca2+ rise [54]. In large animal models, preconditioning induces minimal or no change in the frequency or temporal distribution of ischemic arrhythmias [55,56].

The lack of apparent effects of ischemic preconditioning during ischemia is in sharp contrast with the marked effect described in reperfused myocardium: strikingly reduced cell death, attenuated post-ischemic contractile failure [57], reduced myocardial edema [58] and microvascular dysfunction [59–61]. Thus, although ischemic, or pharmacological preconditioning, must be applied before the onset of ischemia, its protective effect appears to be paradoxically manifested only at the time of reperfusion. This is the opposite to what typically happens with pharmacological treatments that protect against ischemia–reperfusion when given prior to ischemia, as is the case of the Na+/H+ exchanger inhibitors [43,62–64]. In contrast to ischemic preconditioning, treatment with Na+/H+ exchanger inhibitors is protective effect can be demonstrated during the ischemic period as slowed ATP depletion [65], delayed rigor onset [63,65,66] attenuated Na+ and Ca2+ overload [67].

2.4 Cardiomyocyte cell death during myocardial reperfusion: the role of gap junctions
Cardiomyocyte cell death may occur during the first minutes of reperfusion, or later on, several hours after restoration of blood flow. The time-course of cardiomyocyte injury and cell death during myocardial ischemia and reperfusion has been well characterized in different experimental models [68–71].There is evidence that, under most circumstances, the contribution of immediate cell death during myocardial reperfusion to final infarct size is very high. Infarct size varies very little when determined after 90 min or 24 h of reperfusion following transient coronary occlusion [72]. In a series of studies from our laboratory involving 48–50 min of transient coronary occlusion in the pig, infarct size in the absence of interventions was approximately 60% [73,74], 55% [14,63], 35% [75] and 50% [76,77] after 2, 5, 6 and 24 h of reperfusion, respectively. The lack of progression of infarct size during the initial hours following reflow implies that most of it occurs during the first minutes of reflow [69,71]. In fact, reperfused infarcts are mainly composed of areas of contraction band necrosis [78], a histological pattern that reflects hypercontracture [79] and can be demonstrated as soon as 5 min after reflow [80]. Monitoring the end-diastolic length of the reperfused myocardial segment in hearts submitted to transient coronary occlusion has demonstrated that hypercontracture also occurs during the initial minutes of reflow also during ‘in vivo’ coronary reperfusion [80]. In the isolated rat heart, hypercontracture results in a severe increase in end-diastolic ventricular pressure reaching its maximum 2–5 min after reperfusion, and coincides with the peak in the rate of LDH release [81,82].

The mechanisms leading to hypercontracture and sarcolemmal disruption during initial reperfusion have been partially elucidated [40,83]. Restoration of ATP synthesis and normalization of intracellular pH in the presence of an increased cytosolic Ca2+ concentration results in excessive contractile activation, hypercontracture, and sarcolemmal rupture [40]. This is favored by the increased susceptibility to Ca2+ of the sarcomeric proteins and sarcolemmal fragility induced by ischemia–reperfusion, and by osmotic cell swelling [79,84–86]. Increased cytosolic Ca2+ concentration occurs despite an initial rapid reduction caused by sequestration into the sarcoplasmic reticulum, due to additional Ca2+ influx via reverse mode Na+/Ca2+ exchange [87,88], and rapid and large Ca2+ oscillations between SR and cytosol among other causes [87,89]. The role of mitochondria is being actively investigated but has not been yet established. Mitochondria could help to normalize cytosolic Ca2+ concentration by sequestering it, contribute to increase cytosolic Ca2+ by opening of the mitochondrial transition pore, or do both things sequentially [90,91].

Cell-to-cell communication through gap junctions may result in spreading of different types of cell injury, including ischemia in non-cardiac tissue. Several studies have shown that gap junction coupling during cerebral ischemia can result in an amplification of cell injury [92–94]. Cell-to-cell communication can mediate the death of tumor cells adjacent to those directly targeted by different antineoplastic treatments (bystander effect) [95–97]. There is evidence suggesting that gap junction-mediated communication may allow cell-to-cell propagation of cardiomyocyte hypercontracture during ischemia–reperfusion [13,14,98] (Fig. 1). These studies suggested that passage of Na+ through gap junctions from hypercontracting cells to adjacent ones, and subsequent exchange with Ca2+ through reverse mode of Na/Ca exchange, results in propagation of hypercontracture [13]. It appears that this propagation contributes significantly to the final infarct size, since its inhibition with intracoronary heptanol at low concentrations lacking significant effects in single cells reduced cell death and modified infarct geometry [14]. Cell-to-cell interaction was predicted as necessary to explain the continuous geometry of contraction band necrosis in reperfused myocardium [99]. Interestingly, a modification of infarct geometry similar to that observed with heptanol had been earlier described with intracoronary 2',3'-butanodionemonoxime (BDM) [76], a blocker of actin–myosin interaction that has been found to be as well a potent inhibitor of gap junction-mediated intercellular communication in cardiomyocytes [100].


Figure 1
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  		Fig. 1 Diagram showing the suggested contribution of gap junction (GJ) mediated communication to the cellular mechanisms of the main events in the progression of myocardial ischemia, and the consequences of this contribution to the pathophysiology of acute myocardial infarction.

 

   3. Gap junction communication during ischemia and early reperfusion in preconditioned myocardium
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 Abstract
 1. Gap junctions in...
 2. The mechanism of...
 3. Gap junction communication...
4. Delayed cell death...
 5. Conclusion
 References
 
One of the prominent effects of ischemia is to impair gap junction-mediated intercellular communication. Although important efforts have been made to determine the consequences of this effect on the genesis of arrhythmias, the potential consequences of disrupted intercellular communication on cell injury secondary to ischemia–reperfusion have not been investigated in depth.

When myocardium is exposed to severe and prolonged ischemia, electrical coupling between adjacent cardiomyocytes is impaired, propagation of electrical impulse is slowed and eventually blocked, and ventricular arrhythmias appear [12,20,101]. These changes are in close temporal association with the development of rigor contracture [12,20,101]. Changes associated with ischemia (increased Ca2+, acidosis, ATP depletion, accumulation of amphiphilic catabolites) reduce, or even abolish, electrical gap junctional conductance in ‘in vitro’ cell systems [3]. However, it is not known whether and when gap junction-mediated cell communication is completely abolished in ischemic myocardium. Although it seems clear that ischemia impairs electrical cell coupling, gap junction permeability for metabolites and signal molecules cannot be deduced from electrophysiological observations in ischemic tissue. This is because factors, other than electrical coupling (i.e., changes in cellular excitability), importantly contribute to electrophysiological changes in ischemic myocardium [20,101,102]. Obviously, gap junction permeability to large molecules must fall to zero when gap junction conductance reaches zero, but the relationship between both parameters at low conductance, without reaching zero values, is unclear. Thus, the relation between gap junction electrical conductivity and permeability to large molecules is not linear. It has been shown that certain interventions may have opposed actions on the probability of the open state and on the opening diameter, thus increasing electrical conductivity while reducing permeability [24,103].

There is experimental evidence suggesting that Cx43 channels may remain open during energy depletion and ischemia in different cell types including cardiomyocytes [50,92,93]. Using a model of cultured astrocytes, it was recently found [92] that coupling was reduced but never abolished after 2 h of metabolic inhibition, and that chemical communication through gap junctions occurred up to the terminal loss of membrane integrity. Moreover, and interestingly, lowering pH to 6.0 caused no detectable decrease in gap junction permeability. Chemical coupling in astrocytes was corroborated in hippocampal slices during ischemic conditions. Similar results [93] were obtained in neocortices of rats after applying the technique of fluorescent recovery after photobleaching. Although the rate of fluorescence recovery decreased (reflecting a decreased diffusion through gap junctions) they found that astrocytic gap junctions remain open in the anoxic brain. Our group has recently found evidence that gap junction-mediated communication allows synchronization of rigor contracture in end-to-end pairs of freshly isolated cardiomyocytes during simulated ischemia, and that dye coupling persists after development of rigor despite a rise in intracellular Ca2+, depletion of ATP, and acidosis [104]. Dye coupling was also demonstrated by sectioning and exposure to gap junction permeant and impermeant dyes under anoxic conditions in rat myocardium 20 min after the development of ischemic rigor contracture [104].

Although gap junction-mediated cell-to-cell communication may help to synchronize the progression of injury across the ischemic myocardium, its effect on final cell injury has not been established. This synchronization could benefit cells with more severe injury and be detrimental for cells with slower progression of injury. The latter hypothesis is supported by a recent study showing that treatment with the gap junction blocker heptanol immediately before coronary occlusion, rather than at the time of reperfusion, was not protective in the isolated rabbit heart [105].

3.1 Effect of ischemic preconditioning on changes in gap junction-mediated communication induced by ischemia
The mechanisms involved in the regulation of Cx43 permeability are not completely understood. Ischemia induces marked changes in the phosphorylation status of many proteins. There is strong evidence that gap junction gating may be regulated by changes in connexin phosphorylation, although the exact mechanism of this regulation remains obscure. While some studies have observed a reduction of gap junction communication by treatments that reduce connexin phosphorylation [17,100], most recent studies show the opposite. There is compelling evidence that phosphorylation of Cx43 by different protein kinases, including MAP kinase, p34 kinase, and PKG reduces gap junction communication [18,19,23,24,66], while dephosphorylation increases it [21]. Therefore it is conceivable that dephosphorylation of gap junction channels under ischemic conditions would alter their gating properties rendering them less responsive to changes that would normally reduce conductance, as acidosis or increased Ca2+ concentration.

There is a rapidly increasing mass of data on the intracellular signaling cascades triggered by ischemic preconditioning [32]. It is now clear that PKC and a p38 MAPK cascade are activated, either sequentially or in parallel [36] in ischemic preconditioning. The {epsilon} subtype of PKC (PKC-{epsilon}) plays an important role both in the preconditioning cascade [106,107] and in the modulation of gap junction permeability through phosphorylation [108], and it is, thus, conceivable that the effects on ischemia on gap junction communication could be modulated by ischemic preconditioning. There is preliminary experimental evidence supporting this hypothesis. It has been shown that the KATP channel influences the effect of Ca2+ on Cx43 gap junction-mediated communication [109]. More recently, it has been described that brief episodes of preconditioning ischemia can have sustained effects on the amount and distribution of gap junction in cardiomyocytes [110].

However, these changes do not seem to be of great relevance to the progression of cell uncoupling during sustained ischemia. In a recent study the effects of ischemic preconditioning on the changes in myocardial electrical impedance to a 7-kHz current and on conduction velocity induced by ischemia were analyzed in the in situ pig heart and in rat myocardium submitted to ischemia [111]. Ischemic preconditioning did not modify the time course of the changes in myocardial impedance (resistivity or phase shift) (Fig. 2), the onset of conduction blockade, or the distribution of Ib arrhythmias, in agreement with previous studies showing only a minimal delay in the alteration in electrical impedance [112]. Moreover rigor onset was not modified by ischemic preconditioning in either pig or rat myocardium. However, pretreatment with an inhibitor of Na+/H+ exchange induced a marked delay in rigor onset, alteration of electrical impedance and conduction blockade [111]. These results suggest that the lack of effect on gap junction-mediated intercellular communication during ischemia is not an exception within the general lack of effect of ischemic preconditioning on cellular changes induced by ischemia.


Figure 2
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  		Fig. 2 Changes in myocardial electrical impedance (of phase angle shift) in the area at risk induced by 48 min of coronary occlusion ischemia followed by reperfusion in three in situ pig hearts representative of three different treatments: ischemic preconditioning (two cycles of 5 min ischemia and 5 min of reperfusion) (triangles), administration of HOE246 3 mg/kg of body weight 10 min before coronary occlusion (open circles), and control (no treatment)(closed circles). The two thin dashed areas denote the two periods of preconditioning ischemia (in the preconditioned animal), and the broad dashed area correspond to the 48 min of sustained ischemia in the three animals. The abrupt change in phase angle induced by ischemia appeared after 22 min of ischemia in the control and the preconditioned animal (A), and clearly later in the animal pretreated with HOE246 (B).

 
3.2 Effects of ischemic preconditioning on gap junction communication during reperfusion
In contrast to what happens during ischemia, changes in gap junction communication at the time of reperfusion appear to be able to modulate the magnitude of myocardial cell death, and are thus potential candidates to be effectors of ischemic preconditioning against lethal injury. Unfortunately, there is an absolute lack of information about the time course of normalization of gap junction-mediated intercellular communication in cells surviving ischemia–reperfusion.

It is clear that the return to normal function of surviving myocardium implies this normalization. The observation that reoxygenation-induced hypercontracture can propagate to adjacent cells in a gap junction-dependent manner strongly suggests that gap junction communication is already present before cytosolic Ca2+ concentration has returned to normal values [14]. However, it is not known whether this gap junction-mediated communication during early reperfusion is due to persistent residual conductivity at the end of ischemia or to a rapid recovery of gap junction permeability secondary to restoration of normal intracellular (pH, ATP, ionic composition) and extracellular environment (washout of amphipathic catabolites, etc). This latter interpretation is supported by the observation of a sharp normalization during the first few minutes of reperfusion of the alterations in myocardial tissue impedance induced by previous ischemia (Fig. 2, unpublished observation).

It is conceivable that ischemic preconditioning can influence the time-course of normalization of gap junction permeability during the first minutes of reperfusion. Changes in the phosphorylation status of CX43 could result in reduced permeability during initial reperfusion even if ischemic preconditioning does not modify the time-course of uncoupling during the preceding ischemia. During prolonged ischemia, changes in the phosphorylation potential secondary to ATP depletion, activation of phosphatases, changes in ionic composition, and accumulation of amphipathic catabolites among other derangements, could have a dominant effects on gap junction permeability [3] and render specific phosphorylation changes associated to ischemic preconditioning irrelevant. The rapid correction of these abnormalities during the initial minutes of reperfusion would then unmask any possible direct effects of ischemic preconditioning on gap junction-mediated intercellular communication. The potential effects of ischemic preconditioning on gap junction communication during early reperfusion, and their potential role as end-effectors of the protective effect need thus to be investigated. The effects of ischemic preconditioning could also be indirect. For example, cGMP reduces gap junction communication [113–115] and cGMP synthesis and concentration are diminished in myocardium reperfused after sublethal ischemia [116], which could tend to compensate for other changes reducing gap junction coupling. There is recent evidence that ischemic preconditioning attenuates the reduction of cGMP synthesis induced by ischemia [90,117] and that PKG may be involved in the PC cascade upstream of mitoKATP. Increased cGMP synthesis in preconditioned hearts should lead to reduced GJ conductance during initial reperfusion.


   4. Delayed cell death during reperfusion
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 2. The mechanism of...
 3. Gap junction communication...
 4. Delayed cell death...
5. Conclusion
 References
 
Ischemic preconditioning has been found to interfere with the mechanisms of delayed cell death during reperfusion, by reducing apoptosis [118,119] and inflammatory-like reaction [60]. However, there are good reasons to exclude that these are the only or most important mechanisms of the protection afforded by ischemic preconditioning. The relative importance of apoptosis versus necrosis as a cause of myocyte cell death secondary to ischemia–reperfusion has not been established. After some initial reports suggesting that apoptosis could be responsible for most or an important fraction of cell death in reperfused myocardium [120–123], the general opinion has lessened its importance [124]. The evidence that most of cell death occurs within minutes of reflow in the form of contraction band necrosis (see above) is hardly compatible with a prominent role of apoptosis in acute post-reperfusion myocardial infarction. It has been recently observed that ischemia may reduce the susceptibility of cardiomyocytes to exogenous pro-apoptotic stimuli as NO or H2O2 [125]. However, there is increasing awareness that the pathways of necrotic and apoptotic cell death may share many steps, and that there is crossover between [126].

Thus, although previous studies have established that gap junction communication can modulate apoptosis, it is unlikely that changes in this modulation could contribute significantly to the protective effect of ischemic preconditioning against lethal cell injury secondary to transient, prolonged ischemia [127–130].

On the other hand, the potential importance of attenuated inflammatory reaction as an end-effector of ischemic preconditioning is very much limited by the fact that the full protective effect of ischemic preconditioning can be observed in ‘in vitro’ systems and isolated cardiomyocytes.


   5. Conclusion
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 1. Gap junctions in...
 2. The mechanism of...
 3. Gap junction communication...
 4. Delayed cell death...
 5. Conclusion
References
 
The available evidence is consistent with the hypothesis that gap junctions play a role in the pathophysiology of classical preconditioning against lethal injury. Ischemic preconditioning may influence gap junction-mediated intercellular communication by several mechanisms, including activation of different kinase cascades (Fig. 3), most of which tend to reduce intercellular communication. This effect of ischemic preconditioning seems to have no relevant consequences during prolonged ischemia, and does not modify the frequency or temporal distribution of ventricular arrhythmias during this period. However, the modification of gap junction communication during initial reperfusion could limit cell-to-cell spreading of reperfusion-induced hypercontracture, and contribute to the reduced rate of cell death observed in preconditioning hearts.


Figure 3
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  		Fig. 3 Proposed pathways of modulation of the effects of ischemia–reperfusion on gap junction communication in preconditioned myocardium.

 
The potential role of gap junctions as effectors of ischemic preconditioning against lethal injury secondary to ischemia–reperfusion deserves to be investigated in depth. The first step should be to characterize the effect of preconditioning on the changes in cell-to-cell communication induced by ischemia and reperfusion. Subsequent studies could then address the molecular mechanisms of these changes, their relation with the protective effect of preconditioning, and their potential therapeutic exploitation.

Time for primary review 31 days.


   Acknowledgements
 
This article is based on work partially supported by a grant from the Comisión Interministerial de Ciencia y Tecnología, CICYT, SAF 99-102.


   References
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 3. Gap junction communication...
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 5. Conclusion
 References
 

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D. M Yellon and J. M Downey
Spotlight on preconditioning
Cardiovasc Res, August 15, 2002; 55(3): 425 - 428.
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