Refining the molecular organization of the cardiac intercalated disc

Vermij, Sarah H.; Abriel, Hugues; Veen, Toon A.B. van

doi:10.1093/cvr/cvw259

Cited by 157 publications

(162 citation statements)

References 98 publications

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“…The ICD is a structural complex, acting as functional unit to integrate mechanical and electrical coupling of cardiac myocytes. This functional interaction also correlates with structural interactions of proteins of the different subcomplexes . Furthermore, the β 1 ‐adrenergic receptor was also shown to be located at the ICD .…”

Section: Resultsmentioning

confidence: 60%

“…Electrical coupling is mainly maintained by GJs, small cell‐cell‐connecting pores mostly consisting of connexin‐43 (CX43). In addition to enabling electrical current flow to induce contraction, GJs facilitate the intercellular passage of small molecules and ions …”

Section: Introductionmentioning

confidence: 99%

“…In addition to enabling electrical current flow to induce contraction, GJs facilitate the intercellular passage of small molecules and ions. 2,4,5 Mutations in desmosomal proteins are known to be the major cause of arrhythmogenic cardiomyopathy (AC), which is characterized by a progressive loss of cardiac myocytes with cardiac fibrosis, ventricular dilatation and arrhythmia accompanied with a high risk for sudden cardiac death, especially in young athletes. 6 This disease highlights the importance of desmosomes and the ICD for sufficient cardiac function.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

et al. 2019

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Aims Mutations in desmosomal proteins can induce arrhythmogenic cardiomyopathy with life‐threatening arrhythmia. Previous data demonstrated adrenergic signalling to be important to regulate desmosomal cohesion in cardiac myocytes. Here, we investigated how signalling pathways including adrenergic signalling, PKC and SERCA regulate desmosomal adhesion and how this controls gap junctions (GJs) in cardiac myocytes. Methods Immunostaining, Western blot, dissociation assay and multi‐electrode array were applied in HL‐1 cardiac myocytes to evaluate localization, expression and function of desmosomal and GJ components. cAMP levels were determined by ELISA. Results Activation of PKC by PMA or adrenergic signalling increased cell cohesion and desmoglein‐2 and desmoplakin localization at cell‐cell junctions, whereas tryptophan (Trp) treatment to inhibit cadherin binding or inhibition of SERCA by thapsigargin reduced cell cohesion, while cAMP elevation rescued this effect. Despite no changes in protein expression, accumulation of GJ protein connexin‐43 was detectable at cell‐cell contacts in parallel to increased cohesion. Disruption of cell cohesion by Trp, PMA or thapsigargin impaired conduction of excitation comparable to GJ inhibition. cAMP elevation was effective to improve arrhythmia after Trp treatment. Weakened cell cohesion by Trp or depletion of desmoglein‐2 or plakoglobin blocked signalling via the β1‐adrenergic receptor. Moreover, silencing of desmosomal proteins increased arrhythmia and reduced conduction velocity, which were rescued by cAMP elevation. Conclusion These data demonstrate the interplay of GJs, desmosomes and the β1‐adrenergic receptor with regulation of their function by cell cohesion, adrenergic and PKC signalling or SERCA inhibition. These results support the identification of new targets to treat arrhythmogenic cardiomyopathy.

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Section: Resultsmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

et al. 2019

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“…Proper organization of intercalated discs is necessary to maintain normal cell-cell interactions between myocytes and therefore preserve cardiac function [3]. Intercalated discs are composed of adherens junctions, desmosomes, and gap junctions [4]. The classical adhesion receptor present in the adherens junctions and desmosomes is composed of cadherins.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism

Ackermann¹,

Petrosino²,

Manring³

et al. 2017

Journal of Molecular and Cellular Cardiology

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The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFβ1). While TGFβ1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac-specific transgenic mice expressing active TGFβ1 were generated to model the observed increase in activity in the failing heart. Activation of TGFβ1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFβ1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFβ1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38-dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFβ1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non-ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFβ1 activity in the human cardiac ventricle. Overall, we found that TGFβ1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFβ1 and reduce heart failure severity.

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“…The ablation of LRP6 in adult mouse hearts led to cardiac dysfunction and disruption of ID structure, with distorted expression of ID components. The ID, an indispensable structure connecting neighboring cardiomyocytes, fulfills electrical, mechanical and signaling communication between adjacent cells to ensure the coupling of the contraction process of the myocardium (Vermij, Abriel, & van Veen, 2017). IDs are composed of three major parts: gap junction, desmosome and AJ.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein receptor‐related protein 6 is required to maintain intercalated disk integrity

Wang

Zou

et al. 2019

Genes to Cells

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The intercalated disk (ID), a highly organized adhesion structure connecting neighboring cardiomyocytes, fulfills mechanical and electrical signaling communication to ensure normal heart function. Lipoprotein receptor‐related protein 6 (LRP6) is a co‐receptor inducing canonical Wnt/β‐catenin signaling. It was recently reported that LRP6 deficiency in cardiomyocytes predisposes to arrhythmia independent of Wnt signaling. However, whether LRP6 directly regulates the structure of IDs requires further investigation. The aim of the present study was to explore the role of LRP6 in IDs and the potential underlying mechanisms by inducible cardiac‐specific LRP6 knockout mice. The results revealed that LRP6 was predominately expressed in the cell membrane, including the IDs of cardiomyocytes. Tamoxifen‐inducible cardiac‐specific LRP6 knockout mice displayed overt cardiac dysfunction and disruption of ID structure. Further analysis revealed that cardiac LRP6 deficiency induced the imbalance of ID component proteins, characterized by the sharply decreased expression of connexin 43 (Cx43) and the significantly increased expression of N‐cadherin, desmoplakin and γ‐catenin in tissue lysates or membrane fraction from the left ventricle. STRING database analysis indicated that β‐catenin, but no other ID‐associated proteins, interacted with LRP6. Our immunoprecipitation analysis demonstrated that LRP6 strongly interacted with Cx43, N‐cadherin and γ‐catenin, and weakly interacted with β‐catenin, whereas there was no association with desmoplakin. In response to LRP6 deficiency, the recruitment of β‐ or γ‐catenin to N‐cadherin was increased, but they displayed little interaction with Cx43. In conclusion, LRP6 is required to maintain the integrity of ID structure and the balance of ID proteins, and the interaction between LRP6 and Cx43, N‐cadherin and γ‐catenin may be involved in this process.

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Refining the molecular organization of the cardiac intercalated disc

Cited by 157 publications

References 98 publications

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion

TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism

Lipoprotein receptor‐related protein 6 is required to maintain intercalated disk integrity

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