Functional consequences of abnormal Cx43 expression in the heart

Fontes, Magda S.C.; Veen, Toon A.B. van; Bakker, Jacques M.T. de; Rijen, Harold V.M. van

doi:10.1016/j.bbamem.2011.07.039

Cited by 151 publications

(153 citation statements)

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“…Cx43 is the major connexin expressed in the ventricles. Its abnormal expression, typically involving down-regulation and heterogeneous redistribution to the lateral cardiomyocyte membrane, is associated with different forms of chronic heart disease (hypertrophic, dilated, and ischemic cardiomyopathy) and even aging (24)(25)(26). Defective Cx43 expression results in electrical defects in the myocardium and contributes to arrhythmogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Rivera‐Torres

Calvo

Llach

et al. 2016

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

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24 −/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24 −/− progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.Hutchinson-Gilford progeria syndrome | progerin | prelamin A | connexin43 | calcium handling T he LMNA gene encodes A-type lamins (lamin A and lamin C), key components of the mammalian nuclear envelope with important structural and regulatory functions that affect signaling, transcription, and chromatin organization among other processes (1). Mature lamin A is produced from the precursor prelamin A through a series of posttranslational modifications, consisting of sequential farnesylation at the cysteine in the Cysteine-SerineIsoleucine-Methionine motif, cleavage of the Serine-IsoleucineMethionine residues, carboxymethylation of the newly accessible cysteine, and a final proteolytic cleavage by the zinc metallopeptidase STE24 (ZMPSTE24, also called FACE-1) (2).Mutations in the human LMNA gene or defective processing of prelamin A cause a group of diseases termed laminopathies, including the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS), a very rare genetic disorder with an estimated prevalence of 1 in 21 million people (www.progeriaresearch.org). SignificanceDefective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson-Gilford progeria syndrome (HGPS) patients and also occurs during physiological aging. We found overt repolarization abnormalities in HGPS patients at advanced disease stages. Similar alterations were present in proger...

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Section: Discussionmentioning

confidence: 99%

“…Connexins are the pore-forming subunits of gap junctions and essential for proper intercellular electrical coupling between cardiomyocytes and AP spread during each cardiac cycle (23,24). Cx43 is the major connexin expressed in the ventricles.…”

Section: Discussionmentioning

confidence: 99%

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Rivera‐Torres

Calvo

Llach

et al. 2016

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

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“…These gap junctions afford low resistance current flow between cells, with relative conductivity determined by the constituent connexin isoforms, which are expressed with cell type and tissue specificity varying throughout the atria, ventricles, and conduction system [76][77][78][79][80]. Cardiac conduction is thus dependent on the integrity of mechanical junctions between cells, and alterations in connexin expression due to disease [79,[81][82][83] Connexon mechanosensitivity in cardiac cells is unknown, although increased conductivity with stretch has been shown in other cell types [84]. Mechanical loading increases expression of gap junction proteins through hypertrophy processes, which can lead to an increase in conduction velocity [85,86].…”

Section: Cell Scale: Myocyte Electromechanical Couplingmentioning

confidence: 99%

Biomechanics of Cardiac Electromechanical Coupling and Mechanoelectric Feedback

Pfeiffer

Tangney

Omens

et al. 2014

Journal of Biomechanical Engineering

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Cardiac mechanical contraction is triggered by electrical activation via an intracellular calcium-dependent process known as excitation-contraction coupling. Dysregulation of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, electrical dyssynchrony leads to mechanical alterations and exacerbates pump dysfunction in heart failure. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred as cardiac mechanoelectric feedback and thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. At the cellular scale, most investigations of myocyte mechanoelectric feedback have focused on the roles of stretch-activated ion channels, though mechanisms that are independent of ionic currents have also been described. Here we review excitation-contraction coupling and mechanoelectric feedback at the cellular and organ scales, and we identify the need for new multicellular tissue-scale model systems and experiments that can help us to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart.

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“…Electrical coupling by gap junctions is essential for action potential propagation throughout cardiac muscle [1]. Connexin 43 (Cx43) is the major gap junction protein in ventricular myocytes [1].…”

Section: Introductionmentioning

confidence: 99%

AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

Alesutan

Voelkl²,

Stöckigt³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling. Methods: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by “transverse aortic constriction” (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy. Results: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1^-/- mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1^-/- mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK^WT and constitutively active AMPK^γR70Q, but not by catalytically inactive AMPK^αK45R. Conclusion: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.

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Functional consequences of abnormal Cx43 expression in the heart

Cited by 151 publications

References 122 publications

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Biomechanics of Cardiac Electromechanical Coupling and Mechanoelectric Feedback

AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

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