Review articleCardiac cell–cell junctions in health and disease: Electrical versus mechanical coupling
Introduction
The fascinating phenomenon of excitation contraction coupling is subjected to all the individual cardiomyocytes that compose the heart. Upscaling of this manifestation to the well coordinated excitation and contractile performance of the total organ demands our attention to a tiny but very ingeniously orchestrated part of cardiomyocytes: the intercalated disc (ID). Already in the nineteenth century, Engelmann brought forward the concept that the heart was a functional syncytium [1]. Much later, Weidmann suggested, based on Engelmann's concept, that cardiac cells had to be connected by low cell-to-cell resistances [2]. However, it became evident that cardiac cells are not only connected, but also separated by IDs [3], [4]. This apparent lack of cytoplasmic continuity was refuted by Barr and coworkers, who were the first to define the gap junctions in the IDs as the molecular substrate that facilitated the low resistance intercellular pathway [5].
The IDs between individual cardiomyocytes therefore have at least two syncytial functions: 1. to ensure mechanical coupling and 2. to enable fast propagation of electrical impulses throughout the heart. Improper mechanical coupling between myocytes leads to a deteriorated cardiac pump function, while improper electrical coupling may lead to abnormal conduction of the electrical impulse and subsequent development of cardiac arrhythmias.
The ID is a complex and highly orchestrated structure, where multiple proteins interact and form large complexes. In the past years, a number of cardiac disorders have been described, in which defective mechanical coupling between cardiomyocytes leads to degenerative cardiomyopathies that are besides contractile impairment, also characterized by electrical disorders with occurrence of fatal arrhythmias. An example of such complex disorders is arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) [6], [7]. Disturbance of the delicate interplay between mechanical and electrical coupling at the ID seems to be the key feature of these disorders, and has been the subject of multiple human, animal and in vitro studies in the past few years. This review will focus on cardiac cell–cell junctions in health and disease and explores the interaction between electrical and mechanical coupling.
Section snippets
Cardiac junctions
The main site of myocyte interconnection is the ID, situated at the long ends of the cell [3], [4]. In the ID three different protein complexes are apparent that provide mechanical strength and electrical coupling: adherens-, desmosomal-, and gap junctions.
Adherens junctions (AJs) provide a strong mechanical connection of cardiomyocytes via linkage to the actin cytoskeleton, which provides a uniform mechanical strength to the heart [8]. They keep the cells tightly together as the heart expands
Cardiac disorders caused by changes in mechanical junctions
ARVD/C is a progressive disease that can lead to arrhythmias, heart failure and sudden cardiac death. The prevalence of this disease has been estimated to be approximately 1 in 5000 [29]. However, in some regions like e.g. northern Italy, prevalence is much higher, and approaches 1 in 2000. The exact prevalence remains unknown, because diagnosing ARVD/C is difficult, with many cases going un- or misdiagnosed. About 50% of the confirmed cases is familial, based on genetic modifications with an
Spatiotemporal distribution of AJ and GJ
During cardiomyocyte maturation, large changes in the spatiotemporal distribution of GJs and AJs occur. As shown in a study by Angst et al.[43] GJs and AJs are uniformly distributed along the plasma membrane of rat cardiomyocytes at postnatal day 1. At postnatal day 20 GJs are still distributed along the entire plasma membrane, while in contrast AJs concentrate at the developing ID. At postnatal day 90 all three types of cardiac junctions are located primarily at the ID. This process was also
Gap junctions
As indicated in the previous part of this review, changes in the expression patterns of desmosomal or AJ proteins have a strong effect on the formation or stability of GJs. In this paragraph we will summarize the effects of changes in GJ protein expression on proteins in the desmosome and AJ. In a study by Saffitz et al.[74] the effect of diminished expression of Cx43 on GJ number and size is described. In mice heterogeneous for Cx43 especially the number of GJ plaques was decreased and not
Effect of heart failure on electrical and mechanical junctions
Changes in GJ expression and distribution are a common feature during cardiac remodeling and heart failure. Typically, Cx43 expression levels are reduced and Cx43 migrates from the ID to the lateral sides of the cell. A detailed description of GJ remodeling during heart failure is beyond the scope of this review, and has already thoroughly been reviewed by others [82], [83], [84].
While in models in which no genetic modifications have been made to induce heart failure the effects of heart
Concluding remarks
This review summarized data on cardiac cell–cell junctions in health and disease and explored the interaction between electrical and mechanical coupling. Data show that changes in electrical junction expression and distribution do not directly influence the composition of mechanical junctions in the heart, both AJ and desmosomes.
However, alterations in the composition of the AJ had large effects on GJ expression and function. Studies using animal models with affected components of AJ showed
Acknowledgments
This work is financially supported by the Netherlands Heart Foundation grant 2007B139 and the Interuniversity Cardiology Institute of the Netherlands.
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