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Gap junction remodeling and altered connexin43 expression in the failing human heart

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Abstract

Gap junctions (GJ) are important determinants of cardiac conduction and the evidence has recently emerged that altered distribution of these junctions and changes in the expression of their constituent connexins (Cx) may lead to abnormal coupling between cardiomyocytes and likely contribute to arrhythmogenesis. However, it is largely unknown whether changes in the expression and distribution of the major cardiac GJ protein, Cx43, is a general feature of diverse chronic myocardial diseases or is confined to some particular pathophysiological settings. In the present study, we therefore set out to investigate qualitatively and quantitatively the distribution and expression of Cx43 in normal human myocardium and in patients with dilated (DCM), ischemic (ICM), and inflammatory cardiomyopathies (MYO). Left ventricular tissue samples were obtained at the time of cardiac transplantation and investigated with immunoconfocal and electron microscopy. As compared with the control group, Cx43 labeling in myocytes bordering regions of healed myocardial infarction (ICM), small areas of replacement fibrosis (DCM) and myocardial inflammation (MYO) was found to be highly disrupted instead of being confined to the intercalated discs. In all groups, myocardium distant from these regions showed an apparently normal Cx43 distribution at the intercalated discs. Quantitative immunoconfocal analyis of Cx43 in the latter myocytes revealed that the Cx43 area per myocyte area or per myocyte volume is significantly decreased by respectively 30 and 55% in DCM, 23 and 48% in ICM, and by 21 and 40% in MYO as compared with normal human myocardium. In conclusion, focal disorganization of GJ distribution and down-regulation of Cx43 are typical features of myocardial remodeling that may play an important role in the development of an arrhythmogenic substrate in human cardiomyopathies.

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Authors and Affiliations

  1. Max-Planck-Institute, Benekestrasse 2, D-61231, Bad Nauheim, Germany

    Sawa Kostin

  2. Department of Experimental Cardiology, Max-Planck-Institute, Bad Nauheim, Germany

    Markus Rieger, Sebastian Dammer & Jutta Schaper

  3. Department of Cardiac Surgery, Kerckhoff-Clinic, Bad Nauheim, Germany

    Stefan Hein, Manfred Richter, Wölf-Peter Klövekorn & Erwin P. Bauer

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  1. Sawa Kostin
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  2. Markus Rieger
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  3. Sebastian Dammer
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  4. Stefan Hein
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  7. Erwin P. Bauer
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  8. Jutta Schaper
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Kostin, S., Rieger, M., Dammer, S. et al. Gap junction remodeling and altered connexin43 expression in the failing human heart. Mol Cell Biochem 242, 135–144 (2003). https://doi.org/10.1023/A:1021154115673

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