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Remodelling of gap junctions and connexin expression in diseased myocardium.

Severs NJ, Bruce AF, Dupont E, Rothery S - Cardiovasc. Res. (2008)

Bottom Line: Remodelling may take the form of alterations in (i) the distribution of gap junctions and (ii) the amount and type of connexins expressed.Heterogeneous reduction in Cx43 expression and disordering in gap junction distribution feature in human ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models.Disease-related alterations in Cx45 and Cx40 expression have also been reported, and some of the functional implications of these are beginning to emerge.

View Article: PubMed Central - PubMed

Affiliation: National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. n.severs@imperial.ac.uk

ABSTRACT
Gap junctions form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the regular rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are expressed in the heart: connexin43 (Cx43), Cx40 and Cx45 are found in distinctive combinations and relative quantities in different, functionally-specialized subsets of cardiac myocyte. Mutations in genes that encode connexins have only rarely been identified as being a cause of human cardiac disease, but remodelling of connexin expression and gap junction organization are well documented in acquired adult heart disease, notably ischaemic heart disease and heart failure. Remodelling may take the form of alterations in (i) the distribution of gap junctions and (ii) the amount and type of connexins expressed. Heterogeneous reduction in Cx43 expression and disordering in gap junction distribution feature in human ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models. Disease-related alterations in Cx45 and Cx40 expression have also been reported, and some of the functional implications of these are beginning to emerge. Apart from ventricular disease, various features of gap junction organization and connexin expression have been implicated in the initiation and persistence of the most common form of atrial arrhythmia, atrial fibrillation, though the disparate findings in this area remain to be clarified. Other major tasks ahead focus on the Purkinje/working ventricular myocyte interface and its role in normal and abnormal impulse propagation, connexin-interacting proteins and their regulatory functions, and on defining the precise functional properties conferred by the distinctive connexin co-expression patterns of different myocyte types in health and disease.

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(A) Cx43 is down-regulated and ZO-1 up-regulated in end-stage heart failure, giving a significant negative correlation (P = 0.0029; r2 = 0.51). (B) This is associated with an increased interaction of Cx43 with ZO-1 in both non-junctional and gap-junctional fractions as determined by co-immunoprecipitation (The non-junctional fraction is Triton X-100-soluble and represents Cx43 not assembled into gap junctions). DCM, dilated cardiomyopathy; ICM, ischaemic cardiomyopathy. *P = 0.05 vs. controls. From Bruce et al.96
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CVN133F6: (A) Cx43 is down-regulated and ZO-1 up-regulated in end-stage heart failure, giving a significant negative correlation (P = 0.0029; r2 = 0.51). (B) This is associated with an increased interaction of Cx43 with ZO-1 in both non-junctional and gap-junctional fractions as determined by co-immunoprecipitation (The non-junctional fraction is Triton X-100-soluble and represents Cx43 not assembled into gap junctions). DCM, dilated cardiomyopathy; ICM, ischaemic cardiomyopathy. *P = 0.05 vs. controls. From Bruce et al.96

Mentions: A major focus of current research concerns connexin partner proteins, a series of proteins with regulatory properties that interact with the carboxy-terminal domain of Cx43 (review94). This domain houses a series of functionally important sites, notably those involved in channel gating and phosphorylation (a process implicated in diverse roles including trafficking of connexins and junction assembly and degradation). Apart from c-Src and adhesion junction proteins, other connexin binding partners include tubulin, caveolins, and zonula occludens-1 (ZO-1). Carboxy-terminal binding sites for tubulin and associated motor transport proteins mediate trafficking of connexins to the correct destination at the cell surface, while ZO-1 is intimately involved in regulation of gap junction size. In exogenous expression systems, blocking or abolition of the binding of ZO-1 to Cx43 leads to formation of exceptionally large, extensive gap junctions, an effect that is reversed when the capacity to interact is restored.95 In human ventricular myocytes, ZO-1 is localized to the intercalated disc, and a pool of this ZO-1 interacts with Cx43 gap junctions.96 In the failing ventricle, although an association between reduced ZO-1 and Cx43 levels has been reported,97,98 we find that ZO-1 is, in fact, consistently up-regulated, and that the proportion of Cx43 that interacts with ZO-1 is increased (FigureĀ 6).96 ZO-1 appears to act by limiting the recruitment of connexons to the gap junction periphery,95 and in this way may contribute to reduced gap junction size and overall gap junction content in the diseased human heart.96


Remodelling of gap junctions and connexin expression in diseased myocardium.

Severs NJ, Bruce AF, Dupont E, Rothery S - Cardiovasc. Res. (2008)

(A) Cx43 is down-regulated and ZO-1 up-regulated in end-stage heart failure, giving a significant negative correlation (P = 0.0029; r2 = 0.51). (B) This is associated with an increased interaction of Cx43 with ZO-1 in both non-junctional and gap-junctional fractions as determined by co-immunoprecipitation (The non-junctional fraction is Triton X-100-soluble and represents Cx43 not assembled into gap junctions). DCM, dilated cardiomyopathy; ICM, ischaemic cardiomyopathy. *P = 0.05 vs. controls. From Bruce et al.96
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2533424&req=5

CVN133F6: (A) Cx43 is down-regulated and ZO-1 up-regulated in end-stage heart failure, giving a significant negative correlation (P = 0.0029; r2 = 0.51). (B) This is associated with an increased interaction of Cx43 with ZO-1 in both non-junctional and gap-junctional fractions as determined by co-immunoprecipitation (The non-junctional fraction is Triton X-100-soluble and represents Cx43 not assembled into gap junctions). DCM, dilated cardiomyopathy; ICM, ischaemic cardiomyopathy. *P = 0.05 vs. controls. From Bruce et al.96
Mentions: A major focus of current research concerns connexin partner proteins, a series of proteins with regulatory properties that interact with the carboxy-terminal domain of Cx43 (review94). This domain houses a series of functionally important sites, notably those involved in channel gating and phosphorylation (a process implicated in diverse roles including trafficking of connexins and junction assembly and degradation). Apart from c-Src and adhesion junction proteins, other connexin binding partners include tubulin, caveolins, and zonula occludens-1 (ZO-1). Carboxy-terminal binding sites for tubulin and associated motor transport proteins mediate trafficking of connexins to the correct destination at the cell surface, while ZO-1 is intimately involved in regulation of gap junction size. In exogenous expression systems, blocking or abolition of the binding of ZO-1 to Cx43 leads to formation of exceptionally large, extensive gap junctions, an effect that is reversed when the capacity to interact is restored.95 In human ventricular myocytes, ZO-1 is localized to the intercalated disc, and a pool of this ZO-1 interacts with Cx43 gap junctions.96 In the failing ventricle, although an association between reduced ZO-1 and Cx43 levels has been reported,97,98 we find that ZO-1 is, in fact, consistently up-regulated, and that the proportion of Cx43 that interacts with ZO-1 is increased (FigureĀ 6).96 ZO-1 appears to act by limiting the recruitment of connexons to the gap junction periphery,95 and in this way may contribute to reduced gap junction size and overall gap junction content in the diseased human heart.96

Bottom Line: Remodelling may take the form of alterations in (i) the distribution of gap junctions and (ii) the amount and type of connexins expressed.Heterogeneous reduction in Cx43 expression and disordering in gap junction distribution feature in human ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models.Disease-related alterations in Cx45 and Cx40 expression have also been reported, and some of the functional implications of these are beginning to emerge.

View Article: PubMed Central - PubMed

Affiliation: National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. n.severs@imperial.ac.uk

ABSTRACT
Gap junctions form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the regular rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are expressed in the heart: connexin43 (Cx43), Cx40 and Cx45 are found in distinctive combinations and relative quantities in different, functionally-specialized subsets of cardiac myocyte. Mutations in genes that encode connexins have only rarely been identified as being a cause of human cardiac disease, but remodelling of connexin expression and gap junction organization are well documented in acquired adult heart disease, notably ischaemic heart disease and heart failure. Remodelling may take the form of alterations in (i) the distribution of gap junctions and (ii) the amount and type of connexins expressed. Heterogeneous reduction in Cx43 expression and disordering in gap junction distribution feature in human ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models. Disease-related alterations in Cx45 and Cx40 expression have also been reported, and some of the functional implications of these are beginning to emerge. Apart from ventricular disease, various features of gap junction organization and connexin expression have been implicated in the initiation and persistence of the most common form of atrial arrhythmia, atrial fibrillation, though the disparate findings in this area remain to be clarified. Other major tasks ahead focus on the Purkinje/working ventricular myocyte interface and its role in normal and abnormal impulse propagation, connexin-interacting proteins and their regulatory functions, and on defining the precise functional properties conferred by the distinctive connexin co-expression patterns of different myocyte types in health and disease.

Show MeSH
Related in: MedlinePlus