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Cardiovascular Research 2000 48(1):8-10; doi:10.1016/S0008-6363(00)00189-9
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Cardiac gap junctions: good or bad?

G. Taimor*

Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, 35392 Gießen, Germany

* Tel.: +49-641-994-7246; fax: +49-641-994-7239 gerhild.taimor{at}physiologie.med.uni-giessen.de

Received 27 July 2000; accepted 31 July 2000

KEYWORDS Apoptosis; Cardiomyocytes; Gap junctions; Ischemia; Reperfusion

See article by Yasui et al. [30] (pp. 68–76) in this issue.

Gap junctions enable the cytoplasm of individual cells to communicate directly and allow exchange of nutrients, ions, metabolites and small molecules up to about 1000 Da [1]. Connexins, which are coded for by a multigene family, are the subunits of gap junctions. In adult mammalian myocardium four different connexins, connexin43 (Cx43), Cx40, Cx45 and Cx37, have been identified [2]. In heterozygous Cx43+/– mice connexin43 has been shown to be the main conductor of intercellular current in the ventricle [3]. The gap junctions are mainly localized at the intercalated discs of the cardiomyocytes [4].

Although all these details on structure and function of single gap junctions are known, their importance for heart function is a matter of ongoing investigations. Best studied is their role in synchronization of electrical activation and contraction of cardiac myocytes [5]. Gap junctional uncoupling is associated with electrical instability and appearance of arrhythmias [6]. On the other hand gap junctional communication seems to play a role in the development of manifest myocardial cell injury. It has recently been shown that gap junctional uncoupling can limit infarct size in the heart [7]. If gap junctions are also involved in apoptotic cardiac cell death has remained an open question. The study of Yasui et al. [30] in this issue is indeed the first report that examines the influence of gap junctional communication on induction of apoptosis in cardiomyocytes. They show in neonatal cardiomyocyte cultures that inhibition of Cx43 synthesis by antisense oligonucleotides results in a decreased coupling of myocytes and in an increased number of apoptotic cells. The stimulus, inducing apoptosis in this model as well as the exact mechanism of protection remain unclear. Yasui et al. [30] suggest that a dilution of apoptosis-inducing factors through gap junctions into adjacent cells may explain the protective effect. But the protection may also be due to propagation of signals inhibiting apoptosis. Factors described as apoptosis inhibiting in heart like Bcl-2 or FGF [8,9] are too large to pass through gap junctions. And it will be of great interest to further characterize the mechanism of protection and especially to identify the molecule that passes through gap junctions. The model described in the study of Yasui et al. may become a useful tool to identify apoptosis associated signals exchanged between cells which either promote or inhibit apoptosis in adjacent cells.

The findings of Yasui et al. [30] may be surprising, since in other cell types an enhancement of cell–cell coupling through gap junctions has usually been found to increase the number of apoptotic cells, e.g., after Ca2+-overload, oxidative stress or metabolic inhibition [10]. However, when comparing the results two specific aspects of the study of Yasui et al. [30] should be considered: first, in this study no single, defined stimulus for apoptosis induction was added to the cells. Second, the authors are looking at a process that takes several days until apoptosis appears, whereas in other studies apoptosis was induced within 24 h. Although under these specific conditions gap junctions prevent apoptosis induction, the study does not exclude that under different conditions apoptosis might be propagated via gap junctions to adjacent cells in the heart. Factors that are known to induce apoptosis in cardiomyocytes, like calcium [11], cAMP [12] or cGMP [13], are able to pass through gap junctions [14] and may therefore induce apoptosis in neighboring healthy cells. But many of these inducers are also known to close gap junctions [15,16] and may therefore prevent transduction of death signals between cells.

In various cardiac diseases uncoupling of cardiomyocytes is found, e.g., in remodeling myocardium [17], in cardiomyopathic [18] or ischemic hearts [19]. During myocardial infarction Cx43 expression is downregulated [20]. Factors that emerge in the acute phase of myocardial infarction, like lysophosphatidylcholine (LPC), high cytosolic calcium, intracellular acidosis or ATP depletion are known inhibitors of gap junctional communication [15,21–23]. In isolated papillary muscle these factors are believed to contribute to a rapid electrical uncoupling under ischemic conditions [15,24]. However, recovery of ATP, pH and cytosolic calcium in reperfusion results in reopening of gap junctions [7,15].

What are the functional consequences of gap junctional communication in ischemic–reperfused hearts? Reduction of LPC accumulation in ischemic myocardium, which could reduce the uncoupling of gap junctions [21], prevents the occurrence of early ventricular tachycardia or fibrillation [25]. This is a potentially important beneficial effect of cellular uncoupling in ischemic hearts. However, there is also experimental evidence that infarct size can be decreased when coupling of the cells is reduced: the continuous geometry of contraction band necrosis, without necrotic cells scattered around the area of risk, already suggests that cell-to-cell interactions contribute to propagation of necrosis. Consistent with this notion is the finding that reperfusion of isolated ischemic hearts in the presence of the gap junction uncoupler heptanol limits contraction band necrosis [7]. It was also shown in isolated pairs of cardiomyocytes that hypercontracture of cells can propagate from cell to cell by a mechanism communicated via gap junctions [26]. The role of gap junctions for the propagation of apoptotic cell death in ischemic–reperfused hearts has not yet been studied. Neither have the stimuli and mechanisms of apoptosis induction been identified with certainty in ischemic–reperfused myocardium. But many studies consider apoptosis as one contributor to lethal reperfusion injury [27]. Since gap junctions are opened again during reperfusion [7,15] they may contribute to acceleration of apoptotic cell death in this situation. In contrast to the situation of reperfusion during the ischemic period coupling of cardiomyocytes via gap junctions may confer protection against apoptosis. This is because ischemic preconditioning, that reduces infarct size and also apoptosis [28], delays gap junctional uncoupling [15]. The prolonged opening of gap junctions after preconditioning might enable anti-apoptotic factors to spread between cells in the ischemic myocardium. This hypothesis is based on the finding that simulated ischemia has been shown to promote protection against apoptosis-inducing agents in isolated cardiomyocytes [13,29].

In conclusion, gap junctions seem to confer both beneficial and detrimental effects on the heart: in ischemia reduction of coupling makes the heart more prone to arrhythmia but, in reperfused myocardium, inhibition of gap junctions decreases the number of cells dying of necrosis. As we learn from the work of Yasui et al. [30], gap junctions can mediate protection against apoptosis induction in cardiomyocyte cultures. How this protective effect relates to heart diseases implying apoptotic myocardial cell death remains to be investigated.


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