© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Forming the network—gap junctions in the cardiovascular system
Heart Center of the University of Leipzig, Leipzig, Germany
Department of Medical Physiology of the University Medical Center Utrecht, Utrecht, The Netherlands
* Corresponding author. Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Struempellstr. 39 04289 Leipzig, Germany. Tel.: +49-341-1044; fax: +49-341-1452. Email address: dhes{at}medizin.uni-leipzig.de
Received 24 February 2004; accepted 1 March 2004
"Cells live together, but die singly," Engelmann wrote more than a century ago. Actually, this sentence describes very clearly the function of intercellular communication. Intercellular communication is maintained by gap junctional channels that connect neighboring cells and allow electrical and metabolic communication, thus forming a functional syncytium instead of a simple agglomeration of cells. Gap junctional channels are dodecameric channels consisting of two hexameric connexons provided by two neighboring cells. A connexon is made up of six proteins, the so-called connexins. In the heart, this gap junctional communication contributes to the biophysical properties of the tissue, subserving the propagation of the action potential and the maintenance of a regular beating rhythm. Disturbance of gap junctional communication is involved in arrhythmogenesis. Moreover, gap junction channels allow for exchange of metabolites and small molecules. In the vasculature, gap junctions participate in the regulation of vasomotor tone, especially upstream regulation. Finally, gap junctional intercellular communication plays an important role in the immuno-inflammatory pathology of atherosclerosis as outlined in the article by Wong et al. [1] in this issue. Thus, gap junctions play an important role in the physiology and pathophysiology of the cardiovascular system. However, many aspects of the regulation, expression and function of gap junctions are still currently under intensive investigation. Therefore, the present Spotlight Issue of Cardiovascular Research is dedicated to gap junctions and cell–cell communication in the cardiovascular system.
The connexins (Cx) comprise a gene family of 20 members in the mouse and 21 in humans. Cx37, Cx40, Cx43, and Cx45 are the most important in the cardiovascular system, as discussed by Söhl and Willecke [2]. Homozygous loss of Cx43 or Cx45 results in neonatal or embryonic lethality while ablation of Cx37 and Cx40 is non-lethal. Thus, in cardiac cells obtained from Cx43(–/–) mice, the beat-to-beat interval is prolonged and more variable and gap junctional conductance is reduced by about 60% so that the expression of other connexins only partially compensates for the loss of Cx43 [detailed by Vink et al. [3]]. Genetically modified Cx genes result in cardiac abnormalities similar to those observed in certain human diseases. Gros et al. [4] describe how genetically modified mice provide an interesting tool for studying the functions of gap junctions in vivo. In human cardiac disease, Cx43 expression is often reduced, a topic that is treated in this issue by Severs et al. [5]. Another feature of diseased cardiac tissue is a change in the distribution of gap junctions. Thus, in atrial fibrillation changes in the expression of Cx43 or Cx40 have been observed as well as alterations in their distribution, with an irregular expression pattern in the atrial tissue and—on a cellular level—a lateralization of connexins that are normally restricted mainly to the cell poles [6,7]. Similarly, as evidenced by Kostin et al. [8] for human cardiac hypertrophy due to aortic stenosis, lateralization of Cx43 is seen in early stages while reduction in Cx43 expression and heterogeneous spatial distribution are characteristic of later stages. Such changes in the expression level, the ratio of certain connexins (Cx43/Cx40), or the tissue or subcellular distribution are assumed to result in the formation of an arrhythmogenic substrate, since they can lead to alteration of the biophysical properties of the tissue. This takes into account that, electrically, gap junctional channels resemble low-resistance connections. Moreno [9] describes how the situation is even more complex because the various connexins differ with regard to their biophysical properties, such that homomeric and heteromeric channels exhibit different profiles of conductance, gating, and voltage sensitivity depending on the direction of current flow.
The propagation of the cardiac action potential is dependent on the presence of gap junctions and is modified by the uniform or non-uniform anisotropic properties of the tissue and possible coupling of non-cardiomyocytes such as fibroblasts to cardiac cells (discussed by Rohr [10]). Thus, in the course of cardiac ischemia, gap junctional channels uncouple due to a number of factors such as ATP loss, calcium overload, and intracellular acidification. This uncoupling, as described by de Groot and Coronel [11], finally leads to type 1B arrhythmias, especially at moderate levels of uncoupling that allow the arrhythmic impulse to propagate at a low velocity. Another aspect of arrhythmogenesis is enhanced dispersion, which contributes to formation of inhomogeneities that allow reentry circuits to occur. Conrath et al. [12] describe in their article that dispersion due to M-cells can be masked by enhanced coupling. Interestingly, during the chronic phase following cardiac infarction, increasing cell loss occurs in parallel with gap junctional remodeling and fibroblast invasion; in the first days by Cx45-expressing fibroblasts and later by Cx43-expressing fibroblasts (treated by Camelliti et al. [13]). This is proposed to be due to a gap junction-mediated bystander effect for the progressive cell loss. On the other hand, as noted by Schulz and Heusch [14], the cardioprotective mechanism of preconditioning seems to depend on functional Cx43 channels, since protective effects are abolished in Cx43 deficiency.
Another aspect of gap junctional intercellular communication treated in this Spotlight Issue is its regulation. Thus, besides cations such as Ca2+, H+, and Mg2+ that have long been known to affect gap junctional conductance, the review by Delmar [15] describes how protein–protein interactions and inter- and intramolecular interactions play an important role in regulating Cx43 channels. Furthermore, as outlined in other articles in this issue, synthesis, assembly, membrane incorporation, and degradation of gap junctional channels are also regulated. Taken together, we see that gap junctions are not static but represent dynamic structures, permanently changing or adapting the communicative potential of a cell to its changing surroundings. An interesting aspect of this process described by Giepmans [16] in this issue is the interaction between connexins and structural proteins such as microtubules and zonula occludens protein ZO-1, which might help in understanding connexin localization to certain areas within the cell. On the other hand, authors Teunissen and Bierhuizen [17] illustrate how the expression of the various connexin isoforms is regulated on a transcriptional level, and altered transcriptional control may help to explain the changes in connexin expression found in cardiac disease.
To form gap junctional channels, connexins have to be oligomerized and assembled and thereafter trafficked to the Golgi apparatus as described in the article by Martin and Evans [18]. Moreover, the degradation of connexins is also subject to regulation by phosphorylation and ubiquitinylation and represents a highly dynamic process with an estimated half-life for Cx43 of 1.5 h in cardiomyocytes. As pointed out in the article by Berthoud et al. [19], three pathways for degradation exist. While misfolded or abnormally oligomerized connexins are degraded by the proteasome pathway, connexins from early secretory compartments can also be degraded by lysosomes without reaching the plasma membrane. Finally, connexins from the gap junction plaques are internalized and degraded by the lysosomes, although in several cell types the latter is also handled by the proteasome pathway.
Since all of these topics of investigation demonstrate an important role for gap junctional intercellular communication in cardiovascular physiology and pathophysiology, it is obviously interesting to try to modify intercellular communication pharmacologically. To this end, several tools for pharmacological modification have emerged. Thus, it is possible to acutely uncouple gap junctions by a number of agents as well as to open them (or keep them open). Besides these acute modifications, this author (Dhein [20]) describes how it is also possible to influence synthesis, intracellular transport and assembly, or docking of gap junctional proteins so that both acute and chronic pharmacological regulation is feasible. However, this is a relatively young field in gap junction research and little—and sometimes conflicting—data are available on the pathophysiological outcome of such pharmacological interventions. Thus, further research is needed to establish under which conditions and in which type of cardiovascular disease enhanced coupling or uncoupling (acute) or enhanced expression of connexins (chronic) might be therapeutically desired [20].
A final aspect of gap junctional intercellular communication, often neglected, is its importance in the vasculature. Cx37, Cx40, and Cx43 are expressed in the endothelium while Cx37, Cx40, Cx43, and Cx45 are found in the underlying muscle layer. Myoendothelial gap junctions have been found between the endothelium and the underlying smooth muscle layer whose connexin composition is still a matter of debate. Besides participating directly in the control of vascular tone, Haefliger et al. [21] describe how Cx40 may be involved in the function of renin-secreting cells; this became evident from Cx40 modification in a model of renin-dependent hypertension. Moreover, it is known that Cx40 knockout mice may suffer from hypertension. In an original contribution from Slovut et al. [22], sympathetic denervation is shown to lead functionally to enhanced Cx43 expression with concomitant increased spontaneous and agonist-induced oscillatory activity.
Taken together, these articles provide evidence for a central role of gap junctions in the functioning of the cardiovascular system, forming a complex and highly dynamic network of cells.
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