Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction

Eloff, Benjamin C.; Gilat, Eran; Wan, Xiaoping; Rosenbaum, David S.

doi:10.1161/01.cir.0000101926.43759.10

Cited by 103 publications

(130 citation statements)

References 32 publications

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“…Instead, we observed a more pronounced decrease of infarct size by RRNYRRNY compared with IP, indicating that preservation of gap junctional communication may be beneficial in mitoK ATPmediated cardioprotection. Given initial data that preservation of gap junctional communication during ischemia may also prevent cardiac arrhythmias (36) and that RRNYRRNY-related peptides may prevent uncoupling of cardiac gap junctions and action potential propagation block among cardiomyocytes (28), the combined targeting of mitochondrial and gap junctional Cx43 may prove an attractive clinical approach for protection against myocardial ischemia/reperfusion injury.…”

Section: See Retraction Published December 10 2012mentioning

confidence: 99%

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Rottlaender

Boengler²,

Wolny³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Section: See Retraction Published December 10 2012mentioning

confidence: 99%

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Rottlaender

Boengler²,

Wolny³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Numerous studies highlight the importance of GJs in the genesis of cardiac arrhythmias, which has stimulated the search for antiarrhythmics targeting GJ channels (Eloff et al 2003). Several reports show that antiarrhythmic properties of the peptide AAP10 and its analogue ZP123, which is more resistant to proteolytic degradation in the digestive tract, are determined by decreased dispersion of activation and increased velocity of impulse conduction in the heart (Haugan et al 2005).…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

“…In addition, ZP123 reduced the incidents of spontaneous ventricular arrhythmias of ischemic origin and size of infarct scars (Hennan et al 2006). It was suggested that these effects resulted from enhancement of intercellular communication, and it was shown that ZP123 does not affect the normal functioning myocardium but is protective during acidosis and metabolic stress (Eloff et al 2003, Haugan et al 2005). Thus, a new class of antiarrhythmic peptides that act on gap junctional communication may emerge.…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Kreuzberg

Willecke

Bukauskas

2006

Trends in Cardiovascular Medicine

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In mouse heart, four connexins (Cxs), Cx30.2, Cx40, Cx43, and Cx45, form gap junction (GJ) channels for electric and metabolic cell-to-cell signaling. Extent and pattern of Cx isoform expression together with cytoarchitecture and excitability of cells determine the velocity of excitation spread in different regions of the heart. In the SA node, cell-cell coupling is mediated by Cx30.2 and Cx45, which form lowconductance (approximately 9 and 32 pS, respectively) GJ channels. In contrast, the working cardiomyocytes of atria and ventricles express mainly Cx40 and Cx43, which form GJ channels of high conductance (approximately 180 and 115 pS, respectively) that facilitate the fast conduction necessary for efficient mechanical contraction. In the AV node, cell-cell coupling is mediated by abundantly expressed Cx30.2 and Cx45 and Cx40, which is expressed to a lesser extent. Cx30.2 and Cx45 may determine higher intercellular resistance and slower conduction in the SA-and AV-nodal regions than in the ventricular conduction system or the atrial and ventricular working myocardium. Cx30.2 and its putative human ortholog, Cx31.9, under physiologic conditions form unapposed hemichannels in nonjunctional plasma membrane; these hemichannels have a conductance of approximately 20 pS and are permeable to cationic dyes up to approximately 400 Da in molecular mass. Genetic ablation of Cxs confirmed that Cx40 and Cx43 are important in determining the high conduction velocities in atria and ventricles, whereas the deletion of the Cx30.2 complementary DNA led to accelerated conduction in the AV node and reduced the Wenckebach period. We suggest that these effects are caused by (1) a dominant-negative effect of Cx30.2 on junctional conductance via formation of low-conductance homotypic and heterotypic GJ channels, and (2) open Cx30.2 hemichannels in non-junctional membranes, which shorten the space constant and depolarize the excitable membrane.In the mammalian heart, gap junction (GJ) channels mediate electric and metabolic communication between cardiac myocytes, thereby allowing cardiac impulse propagation and coordinated contraction of the chambers. Gap junction channels, which connect the cytosplasms of two adjacent cells and enable the diffusion of molecules up to approximately 1 kDa molecular mass, are composed of two hemichannels or connexons (Kumar and Gilula 1996). Each hemichannel consists of six connexin (Cx) protein subunits that are encoded by a multigene family comprising at least 20 members in the mouse and human genome (Söhl and Willecke 2004). Different Cxs coexpressed in the same tissue can form homotypic (same Cx isotype in both hemichannels), heterotypic (two Cx isotypes form cell-cell

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“…The acidosis-induced increase in APD dispersion was prevented by ZP123 administration in Langendorff-pefused guinea pig hearts. ZP123 diminished conduction velocity slowing and heterogeneous repolarization [148]. AAP10 enhanced gap junction conduction in guinea pig cardiomyocytes [149].…”

Section: The Possible Antiarrhythmic Effects Of Gap Junction Modulatorsmentioning

confidence: 96%

“…Ischaemia is associated with reduced sodium current (I Na ) that may cause conduction block [148] whereas the structural inhomogeneity and the increased gap junction resistance restore conduction [151,152]. On the other hand reduced intercellular coupling can limit the spread of mediators of cell death and this way it may reduce the size of infarction [153].…”

Section: The Possible Antiarrhythmic Effects Of Gap Junction Modulatorsmentioning

confidence: 99%

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

Szentmiklósi¹,

Szentandrássy²,

Hegyi³

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction

Abstract: These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.

Cited by 103 publications

References 32 publications

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

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Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction

Abstract: These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.

Cited by 103 publications

References 32 publications

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Chemistry, Physiology, and Pharmacology of &#946;.-Adrenergic Mechanisms in the Heart. Why are .&#946;-Blocker Antiarrhythmics Superior?

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?