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Cardiovascular Research 2004 62(2):335-344; doi:10.1016/j.cardiores.2003.12.017
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Copyright © 2004, European Society of Cardiology

Connexin 43 and ischemic preconditioning

Rainer Schulz* and Gerd Heusch

Institut für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122, Essen, Germany

* Corresponding author. Tel.: +49-201-723-4521; fax: +49-201-723-4481. Email address: rainer_schulz{at}uni-essen.de

Received 24 September 2003; revised 26 November 2003; accepted 15 December 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 
Connexin 43 (Cx43) is the essential protein to form hemichannels and gap junctions in the myocardium. The phosphorylation status of Cx43 which is regulated by a variety of protein kinases and phosphatases determines hemichannel and/or gap junction conductance and permeability. Gap junctions are involved in cell–cell coupling while hemichannels contribute to cardiomyocyte volume regulation. Cx43-formed channels are involved in ischemia/reperfusion injury, since blockade of a large portion of Cx43-formed channels attenuates ischemic hypercontracture, infarct development and post myocardial infarction remodeling. Ischemic preconditioning's protection also depends on functional Cx43-formed channels, since uncoupling of channels or genetic Cx43 deficiency abolishes infarct size reduction by ischemic preconditioning. The exact underlying mechanism(s) how Cx43 mediates protection remain to be established.

KEYWORDS Connexin; Ischemia; Reperfusion; Preconditioning


   1. Introduction
Top
 Abstract
 1. Introduction
2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 
The present review discusses factors affecting gating properties of connexin 43 (Cx43)-formed channels (hemichannels, gap junctions) and their alterations by single or repetitive periods of myocardial ischemia/reperfusion. The contribution of hemichannels and gap junctions to myocardial ischemia/reperfusion injury, especially in the context of ischemic preconditioning, will be highlighted.


   2. Connexin 43
Top
 Abstract
 1. Introduction
 2. Connexin 43
3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 
Gap junctions play an essential role for normal cardiac function, since through them major ionic fluxes between adjacent cardiomyocytes are spread, thereby allowing electrical synchronization of contraction. Each single gap junction is composed of 12 Cx43 units, assembled in two hexameric connexons (hemichannels) which are contributed one each by the two participating cells (for review, see Ref. [1]). Most connexons are located at the cell's terminal intercalated disks and are involved in gap junction formation. However, gap junctions also exist at the lateral sarcolemma and propagate the electrical activity in the transversal direction. Conductance in pairs of mice myocytes is similar in end-to-end or side-to-side connections [2]. Some unopposed connexons are also located at the lateral sarcolemma and connect the intracellular and extracellular space. Until recently these so-called hemichannels were thought to remain permanently closed in order to avoid cell death [3]; new data, however, have documented the existence of regulated hemichannel opening in cultured cells (for summary, see Ref. [4]). Hemichannels appear to be involved in cellular responses such as the release of cytosolic components, e.g. NAD+ and ATP (for review, see Ref. [5]), activation of cell survival pathways [6] and volume regulation [7].

Cx43 has four transmembrane, two extracellular and three cytosolic (including the amino and carboxy terminus) domains; the residues 1–242 form the plasma channel portion, while the residues 243–382 form the cytosolic tail of Cx43 [8]. The length of the cytosolic tail of Cx43 slightly varies between different species and tissues [9].

Connexins interact with other proteins within the cell. Recent studies suggest an association between Cx43 and the peripheral membrane protein ZO-1 in rat cardiomyocytes [10]. ZO-1—in turn—binds to {alpha}-spectrin, a protein which is highly expressed at the intercalated disk [10,11]. Furthermore, Cx43 co-localizes with fibroblast growth factor (FGF) receptors [12] and cytoskeletal proteins [13] (for review, see Ref. [4]).

In summary, connexons are important for cell–cell coupling, but are also involved in cell signaling and volume regulation.


   3. Regulation of hemichannels and gap junctions
Top
 Abstract
 1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 
Cx43-formed hemichannels are not ion-selective [14] and are permeable to organic ions and molecules of a molecular weight of less than 1000 Da and a maximal diameter of approximately 1.5 nm. The transport of ions and small molecules through hemichannels and gap junctions is mediated by passive diffusion and thus depends on the concentration difference between connected cells and the electrical charge of the moving ions or molecules. The transfer of ions and small molecules further depends on the number of available channels (assembly), their open-probability [15] and the individual channel conductance. The number of available channels depends on the synthesis, transport, half-life and breakdown of Cx43 [4].

Cx43-formed gap junctions exhibit three conductance states: one of 20–30 pS, one of 40–60 pS and one of 70–100 pS [1,16,17]. The conductance of Cx43-formed hemichannels ranges from 31 to 352 pS (for review, see Ref. [18]). More recently, the conductance of fully open hemichannels in HeLa-cells was found to be 220 pS; however, also a sub-state of approximately 75 pS exists between the fully open and the closed state [19], suggesting that hemichannel conductance can be regulated as well.

On Western blot, Cx43 exhibits three bands with molecular weights ranging from 41 to 46 kDa, reflecting the non-phosphorylated (NP, 41 kDa) and a partially (P1, 43 kDa) or highly (P2, 46 kDa) phosphorylated state [20–23].

Single channel conductance as well as cell–cell conductance and permeability can be modulated by the intracellular pH, the intracellular calcium or ATP concentrations and the phosphorylation status of Cx43 (for details, see Tables 1 and 2Go). However, single channel conductance and cell–cell conductance can be affected in the opposite direction. Cell–cell conductance in the presence of decreased single channel conductance might nevertheless be increased by increased single channel open-probability or increased channel assembly. Furthermore, regulatory mechanisms can have opposite effects on cell–cell electrical coupling and dye transfer if they have divergent effects on single channel open-probability and channel pore size [24,25]. Finally, regulatory mechanisms interact and depend on the prevailing circumstances, since acidosis in normal hearts reduces dye transfer between cardiomyocytes, while the same level of acidosis during ischemia does not [26]. Mechanisms, which are involved in the regulation of single channel conductance and cell–cell conductance and permeability, are listed below (for details, see Tables 1 and 2Go, Fig. 1):


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  		Table 1 Changes in single channel conductance, cell–cell (junctional) conductance and permeability as well as Cx43 phosphorylation induced by ionic alterations and activation/inhibition of certain protein kinases or protein phosphatases in cardiomyocytes

 

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  		Table 2 Changes in single channel conductance, cell–cell (junctional) conductance and permeability as well as Cx43 phosphorylation induced by ionic alterations and activation/inhibition of certain protein kinases or protein phosphatases in non-cardiomyocytes

 

Figure 1
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  		Fig. 1 Schematic diagram of protein phosphatases and protein kinases (PK) on opening or closure of connexons. PTK: protein tyrosine kinase; MAPK: mitogen activated protein kinases; CasK: casein kinase; P indicates phosphorylation.

 
3.1. Protein kinase A (PKA)
Cyclic adenosine monophosphate (cAMP) activates PKA, which in turn phosphorylates Cx43 in rat cardiomyocytes [27] but not in mouse fibroblasts [28]. Increases in the cAMP concentration increase electrical conductance between paired cardiomyocytes [25,29,30] and increase cell permeability—assessed as dye transfer—in non-cardiomyocytes [28,31,32]. Apart from increased cell–cell conductance and permeability, cAMP also increases the extent of gap junction formation [28,31,32]; this effect is independent from Cx43 phosphorylation in mouse fibroblasts [28]. Increased cAMP concentration results from its enhanced production following stimulation of adenylyl cyclase or from inhibition of phosphodiesterase III secondary to an increased concentration of cyclic guanosine monophosphate (cGMP) [33–35].

3.2. cGMP-dependent protein kinases (PKG)
At a higher concentration, cGMP activates PKG (for review, see Ref. [34]). cGMP decreases single channel conductance in rat cardiomyocytes [17,25] as well as cell–cell conductance [17,25,29] and permeability [25].

3.3. Protein kinase C (PKC)
PKC isoforms ({alpha} and {varepsilon}) form signaling complexes with Cx43 [36,37] and phosphorylate Cx43 in cardiomyocytes [38–40], resulting in decreased single channel conductance as well as in reduced cell–cell permeability in cardiomyocytes [24,25] and non-cardiomyocytes [41]. On the other hand, electrical conductance between paired cardiomyocytes is increased following PKC activation [24,25,42], which could be explained by differences in the single channel open-probability and pore size following channel phosphorylation.

3.4. Protein tyrosine kinase (PTK)
PTK—such as the src kinase—phosphorylates tyrosine residues 247 and 265 of Cx43, thereby reducing cell–cell conductance and permeability of non-cardiomyocytes [43–46]. Also in paired rat cardiomyocytes, permeability is reduced with phosphorylation of Cx43 by PTK [38,47]. Phosphorylation of Cx43 at its tyrosine residue 265 reduces the binding of Cx43 to ZO-1 and subsequently the expression of Cx43 at the intercalated disks [48]. Reduced intercellular communication following lipopolysaccharide administration is related to Cx43 phosphorylation at tyrosine residues [49].

3.5. Mitogen activated protein kinases (MAPKs)
More recently, MAPKs such as erk [50–53], BMK-1 [54], p38 [37,50] and jnk [55,56] have been implicated in the regulation of Cx43 phosphorylation. BMK-1 phosphorylates the serine residue 255 of Cx43 [54], while other MAPKs contribute to Cx43 phosphorylation of the serine residues 279 and 282 [53,57,58]. Increased phosphorylation of Cx43 by MAPKs reduces cell–cell permeability in non-cardiomyocytes [46,52–54], but increases electrical conductance of paired rat cardiomyocytes [50]. The opposite behavior of cell–cell electrical conductance and cell–cell permeability in general following MAPK-induced Cx43 phosphorylation can be explained by changes in single channel pore size, such small ions might still pass through the channel while larger molecules do not.

3.6. Casein kinase (CasK)
CasK1 contributes to Cx43 phosphorylation at serine residues 325 and 330. Such increased Cx43 phosphorylation leads to increased non-junctional membrane expression of Cx43 and decreased cell–cell conductance in rat kidney cells [59].

3.7. Protein phosphatases (PP)
PP contribute to Cx43 dephosphorylation in rat hearts in vitro [60], and dephosphorylation of Cx43 increases single channel conductance in rat cardiomyocytes [17] and non-cardiomyocytes [61].

Apart from the fact that different protein kinases and protein phosphatases independently contribute to the regulation of single channel conductance and cell–cell conductance and permeability, there exists also a substantial cross talk between the different protein kinase/phosphatase pathways. For example, cGMP not only activates PKG but also activates p38 MAPK which, in turn, can induce PP translocation from the cytosol to the membrane [62]. Similarly, activation of PKC and/or PTK can activate MAPKs [63] which subsequently may induce activation of CasK [64], thereby inhibiting PP [65]. Activation of PP, in turn, dephosphorylates MAPKs, thereby decreasing their activities [66].

3.8. Proton and calcium concentration
Apart from activation of protein kinases, increases in the intracellular proton and calcium concentrations or a decrease in the intracellular ATP concentration gradually decrease cell–cell conductance (Tables 1 and 2)Go. However, while acidosis in normal hearts reduces dye transfer between cardiomyocytes, the same level of acidosis during ischemia does not [26], pointing to an interaction of several of the above regulatory mechanisms.

In summary, the phosphorylation status of Cx43 which is regulated by a variety of protein kinases and phosphatases modulates single channel and/or cell–cell conductance and permeability in non-cardiomyocytes and cardiomyocytes.


   4. Myocardial ischemia/reperfusion injury and its modification by ischemic preconditioning
Top
 Abstract
 1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 
Cardiomyocyte death occurs during ischemia as well as during the subsequent reperfusion [67], with both necrosis and apoptosis contributing to cell death [68]. Loss of cardiomyocyte volume regulation contributes to irreversible ischemic tissue injury [69], and open hemichannels might contribute to the ischemia/reperfusion-induced osmotic imbalance in cardiomyocytes [70,71] as well as astrocytes [3].

Brief episodes of ischemia/reperfusion delay the development of irreversible tissue damage induced by a subsequent more prolonged ischemic period [72]. Apart from the delay in infarct development, ischemic preconditioning also reduces the extent of apoptosis [73–75] and protects against arrhythmias in mice [76], rats [77–79], rabbits [80] and dogs [81]. In pigs, however, [82–85] ischemic preconditioning not only fails to reduce the incidence of ventricular fibrillation during ischemia/reperfusion, but even accelerates the onset of ventricular fibrillation during sustained ischemia and decreases the ventricular fibrillation threshold [82]. An explanation for the observed species differences of the antiarrhythmic properties of ischemic preconditioning is lacking so far.


   5. Ionic alterations and protein kinase activation during ischemia
Top
 Abstract
 1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 
During myocardial ischemia, oxidative substrate metabolism is shifted towards anaerobic glycolysis. As a consequence of increased breakdown of creatine phosphate and ATP and increased anaerobic glycolysis, inorganic phosphate accumulates [86] and intracellular acidosis develops [87]; for significant ATP depletion and acidosis to develop, however, requires several minutes [88]. While the activities of PP [89] and CasK [90] remain unaltered during global ischemia in isolated rabbit hearts [89], the intracellular cAMP concentration increases within the first 5 min of global ischemia in isolated rat hearts, resulting in enhanced PKA activity [91]. Also, the activity of PKC isoforms increases within 5 min of global ischemia in isolated rat hearts [92,93]. PTK and MAPKs have increased activities following 8–10 min ischemia [63,69,94]. At this time, also the intracellular sodium and calcium concentrations start to increase [95–98].

In normoperfused myocardium, most of the Cx43 is in a partially phosphorylated state, i.e. is found on Western blot at 43 kDa. Within the first minutes of ischemia, Cx43 remains in a phosphorylated state [37], although at present a detailed analysis is lacking which specific Cx43 residues are phosphorylated. With prolongation of ischemia, however, Cx43 becomes dephosphorylated [37,99–101], most likely due to an unaltered activity of PP and a reduced energy availability for protein kinases. The time course of progressive Cx43 dephosphorylation is closely related to that of electrical uncoupling in isolated rat hearts [99,100]. However, although ischemia clearly impairs electrical cell coupling, cell–cell permeability in general—as assessed by dye transfer—cannot be easily deduced from electrophysiological observations [102]. Indeed, in isolated rat hearts electrical coupling between cardiomyocytes is reduced following 10 min of global ischemia, while dye transfer between cardiomyocytes persists for up to 45 min of global ischemia [26]. In mice astrocytes, simulated ischemia reduces gap junction communication between cells, but even induces opening of non-junctional hemichannels [3]. Also in isolated cardiomyocytes, simulated ischemia causes opening of hemichannels [70,71]. Opening of hemichannels contributes to the elevation of the intracellular sodium and calcium concentrations during simulated ischemia in rabbit ventricular cardiomyoyctes [70].

With a single channel conductance of more than 100 pS [1,17,19], only ten hemichannels need to be open to produce a millimolar cellular sodium influx [103], and such a millimolar increase in the intracellular sodium concentration has been measured during ischemia in whole hearts [104–106]. The osmotic imbalance resulting from increased AMP, inorganic phosphate and sodium concentrations results in swelling and finally membrane rupture of the ischemic cells.

On top, an increased intracellular calcium concentration in the presence of some remaining or restored energy production can induce cardiomyocyte hypercontracture [67], and opening of gap junctions might be involved in the transmission of factors triggering hypercontracture between adjacent cells [26,107], such as sodium [107]. Indeed, cell–cell transmission of hypercontracture can be attenuated in isolated rat cardiomyocytes, in rat hearts in vitro and in pig hearts in vivo by the gap junction uncoupler heptanol (1–2 mM); in pig hearts in vivo heptanol reduces myocardial shrinkage and infarct size as well [108]. Similar results have been obtained with butanedione monoxime, another gap junction uncoupler [109], in pig hearts in vivo [110].

In summary, early during ischemia gap junctions contribute to the transmission of factors triggering hypercontracture. With prolongation of ischemia, modification of gap junction conductance by dephosphorylation of Cx43 induces electrical uncoupling. While thus ion transfer through gap junctions might be impaired, the transfer of other small molecules (cell–cell permeability in general) remains unaltered. Regulation of hemichannels and gap junctions during ischemia can differ, and opening of hemichannels during simulated ischemia in isolated cells contributes to cell swelling and induction of irreversible tissue injury.


   6. Ionic alterations and protein kinase activation during ischemia in preconditioned myocardium
Top
 Abstract
 1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
7. Cx43 and ischemic...
 References
 
In preconditioned myocardium, the intracellular acidification during the prolonged ischemia is reduced. This reduced intracellular acidification most likely reflects decreased anaerobic glycolysis, since blockade of the increased proton efflux by a sodium-proton exchange inhibitor did not alter the ischemic acidification [111]. Ischemic preconditioning also delays the detrimental rise in the intracellular sodium [95] and calcium concentrations [95–98] during the subsequent prolonged ischemia. The activities of PP remain unaltered during 60 min global ischemia in preconditioned rabbit hearts compared to baseline conditions and non-preconditioned hearts [89]. However, the adenylyl cyclase activity [93] and the accumulation of cAMP and cGMP during the prolonged ischemia are reduced in preconditioned rat hearts [91]. Depending on the preconditioning protocol (single vs. multiple cycles of ischemia/reperfusion), PKC activity during the sustained ischemic insult can be reduced in preconditioned hearts [93]. In contrast, the activities of PTK [94], MAPKs (BMK-1, p38, erk) [90,94] and CasK [90] increase to a greater extent within the first 10 min of the prolonged ischemia in preconditioned than in non-preconditioned myocardium. However, later during the prolonged ischemia, PTK and BMK-1 activities [94] as well as CasK activity [90] fall again below their respective activities in non-preconditioned myocardium. There is also a differential activation of p38MAPK alpha and beta isoforms: while p38MAPK alpha activity is increased during the prolonged ischemia in non-preconditioned and preconditioned myocardium, p38MAPK beta activity is increased only in preconditioned myocardium [37].

From the measured ionic alterations and profiles of protein kinase activation during sustained ischemia in preconditioned hearts one can expect: (1) that secondary to a decreased cGMP concentration and a more rapid and increased MAPK activation single channel and cell–cell conductances are maintained normal for a longer period of time during the sustained ischemia in preconditioned than in non-preconditioned hearts; (2) that secondary to a more rapid and increased PTK activity cell–cell permeability in general—as assessed from dye transfer—is reduced during the sustained ischemia in preconditioned compared to non-preconditioned hearts.


   7. Cx43 and ischemic preconditioning
Top
 Abstract
 1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
References
 
Indeed, both changes in the electrical coupling between cardiomyocytes and in the channel permeability have been demonstrated following ischemic preconditioning. Cx43 dephosphorylation is decreased in preconditioned compared to non-preconditioned myocardium [37,100], and the electrical uncoupling, which is closely related to Cx43 dephosphorylation [99], is almost completely abolished by ischemic preconditioning in rat hearts [100]. Decreased channel permeability could protect cardiomyocytes against sodium and subsequently volume overload, and indeed cardiomyocytes become more resistant towards a hypotonic challenge once they are preconditioned [112]. Also, administration of fibroblast growth factor (FGF)-2, which is known to reduce cell–cell permeability in cardiomyocytes via PTK activation and Cx43 phosphorylation [38,47], mimics ischemic preconditioning's protection in rats [113] and pigs [114] (for review, see Ref. [115]). Finally, even the passage of a "death factor" [102,116] during the sustained ischemia between adjacent cells could be reduced in preconditioned hearts with reduced cell–cell permeability.

An alternative explanation of the protection afforded by Cx43 relates to the preconditioning ischemic period per se rather than the sustained ischemic episode. During the preconditioning ischemia, a "survival factor" [117] could pass through severely ischemic cardiomyocytes via connexons, thereby putting connected cells or cells in close proximity into a protected state. Established factors which are released from cardiomyocytes and can induce a preconditioning phenomenon in cardiomyocytes are calcium ("calcium preconditioning") and adenosine (for review, see Ref. [69]). Indeed, uncoupling of connexons with heptanol in mice [117] or genetic Cx43-deficiency [118,119] abolishes ischemic preconditioning's protection.

It is currently unclear, whether the obvious importance of Cx43 in ischemic preconditioning's protection relates to alterations in gap junction communication or to changes in volume homeostasis. A study in pigs hearts in vivo [120] found protection but no alteration of ischemia-induced changes in cardiac impedance and therefore favored a non-gap junction mediated mechanism. More directly, we have recently seen that ischemic preconditioning's protection is also abolished in isolated cardiomyocytes from heterozygous Cx43-deficient mice, a preparation where no cell–cell communication via gap junctions exists [121].

Apart from the importance of connexons located at the sarcolemma for ischemia/reperfusion injury and ischemic preconditioning's protection, other cellular localizations must be considered as well. In endothelial cells, Cx43 has been identified at the mitochondria, and its expression is increased upon cellular stress [122]. The functional importance of mitochondrial Cx43 is unknown at present, but the importance of mitochondria in ischemia/reperfusion injury [123] and ischemic preconditioning's protection [124,125] is well accepted. The cytoplasmic tail of Cx43 interacts with the nucleus, thereby inhibiting cellular growth [126]. Alteration of protein synthesis is of no importance for acute ischemia/reperfusion injury and early ischemic preconditioning. However, protein synthesis is important in delayed preconditioning [127], and it is of major importance for the remodeling phase following restoration of blood flow, and indeed genetic Cx43 deficiency impacts on left ventricular remodeling [128].

In summary, Cx43-formed channels are involved in ischemia/reperfusion injury and ischemic preconditioning's protection. The exact underlying mechanism(s), how in fact Cx43 mediates protection, remain to be established.


   Notes
 
Time for primary review 26 days


   References
Top
 Abstract
 1. Introduction
 2. Connexin 43
 3. Regulation of hemichannels...
 4. Myocardial...
 5. Ionic alterations and...
 6. Ionic alterations and...
 7. Cx43 and ischemic...
 References
 

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