Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction

Stein, Mèra; Veen, Toon A.B. van; Remme, Carol Ann; Boulaksil, Mohamed; Noorman, Maartje; Stuijvenberg, Leonie van; Nagel, Roel van der; Bezzina, Connie R.; Hauer, Richard N.W.; Bakker, Jacques M.T. de; Rijen, Harold V.M. van

doi:10.1093/cvr/cvp124

Cited by 57 publications

(55 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further demonstrate increased sensitivity to G j uncoupling. Therefore, regardless of the mechanism, this study offers a potential explanation for conflicting results concerning the -G j relationship (6,14,18,29,38,41,42,44).…”

Section: Resultsmentioning

confidence: 90%

Interstitial volume modulates the conduction velocity-gap junction relationship

Veeraraghavan

Salama

Poelzing

2012

American Journal of Physiology-Heart and Circulatory Physiology

126

View full text Add to dashboard Cite

Cardiac conduction through gap junctions is an important determinant of arrhythmia susceptibility. Yet, the relationship between degrees of Gj uncoupling and conduction velocity (θ) remains controversial. Conflicting results in similar experiments are normally attributed to experimental differences. We hypothesized that interstitial volume modulates conduction velocity and its dependence on Gj. Interstitial volume (VIS) was quantified histologically from guinea pig right ventricle. Optical mapping was used to quantify conduction velocity and anisotropy (ARθ). Albumin (4 g/l) decreased histologically assessed VIS, increased transverse θ by 71 ± 10%, and lowered ARθ. Furthermore, albumin did not change isolated cell size. Conversely, mannitol increased VIS, decreased transverse θ by 24 ± 4%, and increased ARθ. Mannitol also decreased cell width by 12%. Furthermore, mannitol was associated with spontaneous ventricular tachycardias in three of eight animals relative to zero of 15 during control. The θ-Gj relationship was assessed using the Gj uncoupler carbenoxolone (CBX). Whereas 13 μM CBX did not significantly affect θ during control, it slowed transverse θ by 38 ± 9% during mannitol (edema). These data suggest changes in VIS modulate θ, ARθ, and the θ-Gj relationship and thereby alter arrhythmia susceptibility. Therefore, VIS may underlie arrhythmia susceptibility, particularly in diseases associated with gap junction remodeling.

show abstract

Section: Resultsmentioning

confidence: 90%

Interstitial volume modulates the conduction velocity-gap junction relationship

Veeraraghavan

Salama

Poelzing

2012

American Journal of Physiology-Heart and Circulatory Physiology

126

View full text Add to dashboard Cite

show abstract

“…Second, there was a difference with previous studies using similar mice with a genetically induced 50% reduction in Cx43 expression 16 or a combined 50% reduction in Cx43 and Nav1. 5,32 in which impulse conduction was not (or hardly) disturbed. Interestingly, fibrosis was not found in these mice.…”

Section: Decreased Cx43 Expression Leads To Enhanced Fibrosis and Arrmentioning

confidence: 96%

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

Jansen

Veen

Jong

et al. 2012

Circ: Arrhythmia and Electrophysiology

View full text Add to dashboard Cite

Background-Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction expression and increased collagen deposition. We hypothesized that reduced connexin43 (Cx43) expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (transverse aortic constriction [TAC]) mouse model. Methods and Results-The Cx43fl/fl and Cx43 CreER(T)/fl mice were aged 18 to 21 months or, at the age of 3 months, either TAC or sham operated and euthanized after 16 weeks. Epicardial activation mapping of the right and left ventricles was performed on Langendorff perfused hearts. Sustained ventricular arrhythmias were induced in 0 of 11 aged Cx43 fl/fl and 10 of 15 Cx43Cre-ER(T)/fl mice (PϽ0.01). Cx43 expression was reduced by half in aged Cx43 CreER(T)/fl compared with aged Cx43 fl/fl mice, whereas collagen deposition was significantly increased from 1.1Ϯ0.2% to 7.4Ϯ1.3%. Aged Cx43CreER(T)/fl mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43CreER(T)/fl mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0Ϯ1.2% versus 0.4Ϯ0.06%), but this increase was significantly higher in Cx43CreER(T)/fl mice (10.8Ϯ1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1␣2 mRNA levels were higher in TAC-operated Cx43HZ mice. Conclusions-Reduced cellular coupling results in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction in homogeneity and proarrhythmia. (Circ Arrhythm Electrophysiol. 2012;5:380-390.)Key Words: arrhythmia Ⅲ collagen Ⅲ electrophysiology mapping Ⅲ connexin43 Ⅲ fibroblast I n the heart, the highly orchestrated propagation of the electric impulse balances on the delicate interplay between excitability, cell-to-cell coupling, and architecture of myocardial tissue. An important aspect of the myocardial architecture is interstitial collagen (fibrosis), which, together with connexin43 (Cx43), determines cell-to-cell coupling in ventricular myocardium. Under normal physiological conditions, the amount of collagen between the cardiomyocytes is low (Ͻ1% of total tissue volume) but contributes to the structural organization of the heart and the anisotropic character of impulse propagation. We recently showed that, in senescent mouse hearts, collagen content was increased (200%) and Cx43 expression was decreased (50%), changes that were associated with increased inducibility of ventricular tachycardias. 1 On the other hand, when the excessive deposition of fibrosis was prevented through long-term inhibition of the renin-angiotensin-aldosterone system, the normal pattern of Cx43 expression was preserved and arrhythmia vulnerability was strongly red...

show abstract

“…We identified that activation of Tyk2 by Ang II in vitro causes an increase in Cx43 protein level via the STAT3 pathway. Other in vitro examples of an increase in Cx43 protein level include exposing freshly isolated aortas of wildtype mice to Ang II for 4 h and the aorta smooth muscle cell line A7r5 to Ang II from 2 to 48 h (maximum expression was observed at 4 h and was maintained to the last time point of 48 h) (72,73). Conversely, chronic exposure of Ang II in animal models shows a decrease in the protein level of Cx43.…”

Section: Tyk2 Phosphorylates Cx43mentioning

confidence: 99%

Regulation of Connexin43 Function and Expression by Tyrosine Kinase 2

Spagnol

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular weight metabolites (Ͻ1 kDa) between adjacent cells. They provide an intercellular pathway for the propagation and/or amplification of signal transduction cascades triggered by cytokines, growth factors, and other cell-signaling molecules involved in growth regulation and development. Gap junctions are formed by the apposition of connexons from adjacent cells, where each connexon is formed by six connexin proteins. Connexins are tetraspanning transmembrane proteins with intracellular N and C termini (CT). 2 There are 21 human isoforms, and although there is significant sequence homology among connexins, their major divergence occurs in the cytoplasmic domains. Connexin43 (Cx43), the most ubiquitously expressed connexin isoform, has been well studied in terms of structure, function, and regulation (1).Cx43 channels can be regulated by a variety of molecules and physiological conditions (e.g. Ca 2ϩ , pH, and intercellular voltage), including through phosphorylation (2, 3). All stages of the Cx43 life cycle (i.e. trafficking, assembly/disassembly, degradation, and channel gating (3)), as well as the regulation of electrical and metabolic coupling and of interactions with other proteins, involve phosphorylation. The Cx43CT is differentially phosphorylated on at least 20 residues, and significant progress has been achieved in characterizing the kinases involved (2, 4 -6). Unfortunately, an understanding of the mechanism(s) by which Cx43 phosphorylation alters channel function is lacking. Several problems contributing to this difficulty include the transient nature of a particular CT phosphorylation state, the ability of many kinases to phosphorylate more than one CT residue, the ability of various kinases to phosphorylate the CT at the same time, and the inability to precisely control which residues are phosphorylated. Strategies employed to overcome these difficulties include the use of phospho-specific CT antibodies (7) and short CT phosphopeptides (8, 9). Also well appreciated is the use of Asp (or Glu) substitutions as a mimetic for phosphorylation (10, 11).The negative charge of the phosphate could affect the permeability of ions through the pore, alter the structure of the transmembrane ␣-helices to influence pore size, or modify the binding affinities of molecular partners involved in Cx43 regulation. Notably, if phosphorylation modifies protein interactions to affect the kinetics of channel assembly/disassembly or degradation, cell-to-cell communication will also be altered. Evidence has emerged that a phosphate can directly block the Cx43CT interaction with ZO-1 (9) and tubulin (8) or enhance the interaction with Nedd4 (12, 13). This information is critical because a particular cellular condition can be correlated with a specific Cx43 phosphorylation status to understand which proteins will and will not interact to affect regulation of Cx43. Numerous serine protein kinases have been identified as...

show abstract

Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction

Abstract: Reduction of both electrical coupling and excitability results in normal conduction velocity parallel to fibre orientation but in pronounced conduction slowing transverse to fibre orientation in RV only, although this does not affect arrhythmogeneity.

Cited by 57 publications

References 43 publications

Interstitial volume modulates the conduction velocity-gap junction relationship

Interstitial volume modulates the conduction velocity-gap junction relationship

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

Regulation of Connexin43 Function and Expression by Tyrosine Kinase 2

Contact Info

Product

Resources

About