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Phosphatidylinositol-bisphosphate regulates intercellular coupling in cardiac myocytes

  • Cardiovascular Physiology
  • Published:
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Abstract

Changes in the lipid composition of cardiac myocytes have been reported during cardiac hypertrophy, cardiomyopathy, and infarction. Because a recent study indicates a relation between low phosphatidylinositol-bisphosphate (PIP2) levels and reduced intercellular coupling, we tested the hypothesis that agonist-induced changes in PIP2 can result in a reduction of the functional coupling of cardiomyocytes and, consequently, in changes in conduction velocity. Intercellular coupling was measured by Lucifer Yellow dye transfer in cultured neonatal rat cardiomyocytes. Conduction velocity was measured in cardiomyocytes grown on microelectrode arrays. Intercellular coupling was reduced by angiotensin II (43.7 ± 9.3%, N = 11) and noradrenaline (58.0 ± 10.7%, N = 11). To test if reduced intercellular coupling after agonist stimulation was caused by PIP2-depletion, myocytes were stimulated by angiotensin II (57.3 ± 5.7%, N = 14) and then allowed to recover in medium with or without wortmannin (an inhibitor of PIP2 synthesis). Intercellular coupling fully recovered in control medium (102.1 ± 8.9%, N = 10), whereas no recovery occurred in the presence of wortmannin (69.3 ± 7.8%, N = 12). Inhibition of PKC, calmodulin, or arachidonic acid production did not affect the response to either angiotensin II or noradrenaline. Furthermore, decreasing or increasing PIP2 also decreased and increased intercellular coupling, respectively. This supports the role of PIP2 in the regulation of intercellular coupling. In beating myocytes, conduction velocity was reduced by angiotensin II stimulation, and recovery after wash out was prevented by inhibition of PIP2 production. Reductions in PIP2 inhibit intercellular coupling in cardiomyocytes, and stimulation by physiologically relevant agonists reduces intercellular coupling by this mechanism. The reduction in intercellular coupling lowered conduction velocity.

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Acknowledgement

We thank Professor Donald Marsh for valuable suggestions and comments to the manuscript. Ninna Buch Petersen and Trine Eidsvoll are thanked for excellent technical assistance.

Grants

This work was supported by: The Danish National Research Foundation; The John and Birthe Meyer Foundation; The Danish Natural and Health Sciences Research Councils; The Velux Foundation; The Danish Heart Association; The Novo Nordisk Foundation; The A.P. Møller Foundation.

Disclosures

There are no conflicts of interest.

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Authors and Affiliations

  1. The Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Johannes P. Hofgaard, Sarah Mollerup, Helene Korvenius Jørgensen, Søren Peter Olesen, Niels-Henrik Holstein-Rathlou & Morten Schak Nielsen

  2. Department of Cellular and Molecular Physiology, Stricht School of Medicine, Loyola University Chicago, Chicago, IL, USA

    Kathrin Banach

  3. The Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Biomedical Sciences, Blegdamsvej 3C, DK-2200, Copenhagen, Denmark

    Morten Schak Nielsen

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  1. Johannes P. Hofgaard
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Correspondence to Morten Schak Nielsen.

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Hofgaard, J.P., Banach, K., Mollerup, S. et al. Phosphatidylinositol-bisphosphate regulates intercellular coupling in cardiac myocytes. Pflugers Arch - Eur J Physiol 457, 303–313 (2008). https://doi.org/10.1007/s00424-008-0538-x

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