Characterization of Gap Junction Remodeling in Epicardial Border Zone of Healing Canine Infarcts and Electrophysiological Effects of Partial Reversal by Rotigaptide

Macia, Esther; Dolmatova, Elena; Cabo, Cándido; Sosinsky, Alexandra Z.; Dun, Wen; Coromilas, James; Ciaccio, Edward J.; Boyden, Penelope A.; Wit, Andrew L.

doi:10.1161/circep.110.959312

Cited by 33 publications

(29 citation statements)

References 53 publications

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“…Consistent with previous descriptions (30,47), we identified decreased Cx-43 density, and extensive lateralization in the peri-infarct zones mapped. CV in this region (as measured by changes in AT) was increased by RSGS in a wavefront-dependent manner.…”

Section: Discussionsupporting

confidence: 92%

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ajijola

Lux

Khahera

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n ϭ 12) or anterior myocardial infarction (MI, n ϭ 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CV L) was increased by RSGS (0.98 Ϯ 0.11 vs. 1.2 Ϯ 0.14m/s, P Ͻ 0.001) but not transverse CV (CV T). This increase was abrogated by ␤-adrenergic receptor and gap junction (GJ) blockade. Neither CV L nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 Ϯ 37 vs. 322 Ϯ 30 ms, P Ͻ 0.001, and 423 Ϯ 36 vs. 398 Ϯ 36 ms, P ϭ 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 Ϯ 1.2 vs. 17.3 Ϯ 1.6 ms, P ϭ 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P Ͻ 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic periinfarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.

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Section: Discussionsupporting

confidence: 92%

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ajijola

Lux

Khahera

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…The amount of pSer368Cx43 was increased in ischemic hearts in rats and, whereas pSer368Cx43 remained predominantly at intercalated disks, there was an increase in Cx43 localization to the lateral plasma membrane (6). Characterization of Cx43 remodeling, in the epicardial border zone of healing canine infarcts 5 days after coronary occlusion, was characterized by a decrease in Cx43 protein, lateralization, and increased Cx43 phosphorylation at Ser-368 (57).…”

Section: Discussionmentioning

confidence: 94%

Protein Kinase Cδ-mediated Phosphorylation of Connexin43 Gap Junction Channels Causes Movement within Gap Junctions followed by Vesicle Internalization and Protein Degradation

Cone

Cavin

Ambrosi

et al. 2014

Journal of Biological Chemistry

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Background: Connexin43, a ubiquitous gap junction protein, is phosphorylated by protein kinase C on serine 368. Results: After PKC␦ activation, phospho-Ser-368 Connexin43 channels segregated into the gap junction center and were subsequently internalized and degraded. Conclusion: PKC␦ phosphorylation triggered internalization and degradation of Connexin43 channels without dephosphorylation. Significance: Differential phosphorylation events are used to sort and traffic Connexin43 channels within gap junctions and into the cytoplasm.

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“…After electrical mapping of the EBZ to identify the CCP and OP of re-entrant circuits, the heart was rapidly removed and tissue was obtained by shaving off a 2-to 3-mm-thick sample with a fine razor from the surface of the infarcted region (3,5,15). Five normal dogs were used as controls (19,30).…”

Section: Methodsmentioning

confidence: 99%

Myofibroblasts cause heterogeneous Cx43 reduction and are unlikely to be coupled to myocytes in the healing canine infarct

Baum

Long²,

Cabo

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Following myocardial infarction (MI) inflammatory responses transform cardiac fibroblasts to myofibroblasts, which in vitro studies show form heterocellular gap junctions with cardiac myocytes via Connexin43 (Cx43). The ability to form heterocellular junctions in the intact heart and the impact of these junctions on propagation is unclear. We used a canine model of MI and characterized the distribution and quantity of myofibroblasts in surviving epicardial cells [epicardial border zone (EBZ)]. We found a significant increase in myofibroblasts within the EBZ and no gap junction plaques between myofibroblasts and myocytes. Because myofibroblasts produce IL-1β, which downregulates Cx43, we asked whether myofibroblast proliferation causes loss of Cx43 near myofibroblast clusters. In vitro studies showed that IL-1β caused loss of Cx43 and reduced coupling. Western blot showed a significant increase of IL-1β in the EBZ, and immunohistochemistry showed a loss of Cx43 in regions of myofibroblasts in the intact heart. Additionally, dye studies in intact heart showed no coupling between myocytes and myofibroblasts. To quantify the effect of myofibroblasts on propagation we used a two-dimensional subcellular computer model of the EBZ, which showed that heterogeneities in myofibroblast density lead to conduction abnormalities. In conclusion, an increase of myofibroblasts in the infarcted heart causes heterogeneous Cx43 levels, possibly as a result of the release of IL-1β and decreased cell-cell communication, which leads to conduction abnormalities following MI.

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Characterization of Gap Junction Remodeling in Epicardial Border Zone of Healing Canine Infarcts and Electrophysiological Effects of Partial Reversal by Rotigaptide

Cited by 33 publications

References 53 publications

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Protein Kinase Cδ-mediated Phosphorylation of Connexin43 Gap Junction Channels Causes Movement within Gap Junctions followed by Vesicle Internalization and Protein Degradation

Myofibroblasts cause heterogeneous Cx43 reduction and are unlikely to be coupled to myocytes in the healing canine infarct

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