Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

Vreeker, Arnold; Stuijvenberg, Leonie van; Hund, Thomas J.; Mohler, Peter J.; Nikkels, Peter G. J.; Veen, Toon A.B. van

doi:10.1371/journal.pone.0094722

Cited by 108 publications

(94 citation statements)

References 39 publications

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“…38 This is similar to human hearts where redistribution of Cx43 from the entire cell surface to the intercalated disc takes also place during postnatal development and continues to ≈7 years of age. 39,40 Consistent with this we observed punctate staining of Cx43 on the ventricular cardiomyocyte surface in newborn control and Cx43+/E42K hearts with no obvious differences in expression or localization between the genotypes (Figure 4). In contrast to Cx43E42K-mutated mouse hearts, in the human Cx43E42K victim's heart a patchy Cx43 protein expression pattern was reported suggesting 20 It is possible that the patchy Cx43 staining pattern observed in the myocardial tissue from the Cx43E42K victim results from poor quality of necropsy tissue.…”

Section: Discussionsupporting

confidence: 82%

Human Connexin43E42K Mutation From a Sudden Infant Death Victim Leads to Impaired Ventricular Activation and Neonatal Death in Mice

Lübkemeier

Bosen

Kim

et al. 2015

Circ Cardiovasc Genet

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Background-Sudden infant death syndrome (SIDS) describes the sudden, unexplained death of a baby during its first year of age and is the third leading cause of infant mortality. It is assumed that ≤20% of all SIDS cases are because of cardiac arrhythmias resulting from mutations in ion channel proteins. Besides ion channels also cardiac gap junction channels are important for proper conduction of cardiac electric activation. In the mammalian heart Connexin43 (Cx43) is the major gap junction protein expressed in ventricular cardiomyocytes. Recently, a novel Connexin43 loss-of-function mutation (Cx43E42K) was identified in a 2-month-old SIDS victim. Methods and Results-We have generated Cx43E42K-expressing mice as a model for SIDS. Heterozygous cardiac-restricted Cx43E42K-mutated mice die neonatally without major cardiac morphological defects. Electrocardiographic recordings of embryonic Cx43+/E42K mice reveal severely disturbed ventricular activation, whereas immunohistochemical analyses show normal localization and expression patterns of gap junctional Connexin43 protein in the Cx43E42K-mutated newborn mouse heart. Conclusions-Because we did not find heterogeneous gap junction loss in Cx43E42K mouse hearts, we conclude that the Cx43E42K gap junction channel creates an arrhythmogenic substrate leading to lethal ventricular arrhythmias. The strong cardiac phenotype of Cx43E42K expressing mice supports the association between the human Cx43E42K mutation and SIDS and indicates that Connexin43 mutations should be considered in future studies when SIDS cases are to be molecularly explained.

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Section: Discussionsupporting

confidence: 82%

Human Connexin43E42K Mutation From a Sudden Infant Death Victim Leads to Impaired Ventricular Activation and Neonatal Death in Mice

Lübkemeier

Bosen

Kim

et al. 2015

Circ Cardiovasc Genet

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“…gap junctions, adherens junctions and desmosomes— that enable electro-mechanical coupling [70]. Connexin-43 is the predominant cardiac gap junction protein.…”

Section: Cardiac Cell Maturitymentioning

confidence: 99%

“…Connexin-43 is the predominant cardiac gap junction protein. Gap junctions are clusters of closely-packed transmembrane intercellular channels that enable rapid propagation of the action potential by permitting the movement of low molecular weight materials between cells [70] (Figure 1C). N-cadherin is an important adherens junction protein.…”

Section: Cardiac Cell Maturitymentioning

confidence: 99%

Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues

Feric

Radišić

2016

Advanced Drug Delivery Reviews

208

200

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Engineering functional human cardiac tissue that mimics the native adult morphological and functional phenotype has been a long held objective. In the last 5 years, the field of cardiac tissue engineering has transitioned from cardiac tissues derived from various animal species to the production of the first generation of human engineered cardiac tissues (hECTs), due to recent advances in human stem cell biology. Despite this progress, the hECTs generated to date remain immature relative to the native adult myocardium. In this review, we focus on the maturation challenge in the context of hECTs, the present state of the art, and future perspectives in terms of regenerative medicine, drug discovery, preclinical safety testing and pathophysiological studies.

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“…N-cadherin expression and localization at cell-cell contacts is associated with increased stability of β-catenin and decreased expression of α-SMA (Xu et al, 2012). CFs form N-cadherin-mediated interactions with CMs, which influences CM structure and contractility during development, normal function and disease (Chopra et al, 2011;Kudo-Sakamoto et al, 2014;Vreeker et al, 2014). In a recent study, N-cadherin bonds between CFs and CMs were shown to dynamically deform CM membranes in response to MyoFB contraction and induce a measurable slowing of CM conduction velocity (Thompson et al, 2014).…”

Section: Cadherins Sense Intercellular Forcesmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

Cited by 108 publications

References 39 publications

Human Connexin43E42K Mutation From a Sudden Infant Death Victim Leads to Impaired Ventricular Activation and Neonatal Death in Mice

Human Connexin43E42K Mutation From a Sudden Infant Death Victim Leads to Impaired Ventricular Activation and Neonatal Death in Mice

Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

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