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Systemic, but not cardiomyocyte-specific, deletion of the natriuretic peptide receptor guanylyl cyclase A increases cardiomyocyte number in neonatal mice

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Abstract

Guanylyl cyclase A (GC-A), the receptor for atrial and B-type natriuretic peptides, is implicated in the regulation of blood pressure and cardiac growth. We used design-based stereological methods to examine the effect of GC-A inactivation on cardiomyocyte volume, number and subcellular composition in postnatal mice at day P2. In mice with global, systemic GC-A deletion, the cardiomyocyte number was significantly increased, demonstrating that hyperplasia is the main cause for the increase in ventricle weight in these early postnatal animals. In contrast, conditional, cardiomyocyte-restricted inactivation of GC-A had no significant effect on ventricle weight or cardiomyocyte number. The mean volume of cardiomyocytes and the myocyte-related volumes of the four major cell organelles (myofibrils, mitochondria, nuclei and sarcoplasm) were similar between genotypes. Taken together, systemic GC-A deficiency induces cardiac enlargement based on a higher number of normally composed and sized cardiomyocytes early after birth, whereas cardiomyocyte-specific GC-A abrogation is not sufficient to induce cardiac enlargement and has no effect on number, size and composition of cardiomyocytes. We conclude that postnatal cardiac hyperplasia in mice with global GC-A inactivation is provoked by systemic alterations, e.g., arterial hypertension. Direct GC-A-mediated effects in cardiomyocytes seem not to be involved in the regulation of myocyte proliferation at this early stage.

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Acknowledgments

The authors wish to thank Susanne Kuhlmann, Christa Lichtenberg and Katharina Völker for expert technical assistance with the preparation of hearts and microscopic sections. This study was supported by the DFG via the excellence cluster REBIRTH (to CM), by the Bundesministerium für Bildung und Forschung (BMBF 01 EO1004) and the DFG (SFB 688) (to MK).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All animal experiments were carried out according to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health and were approved by the local animal care committee.

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Authors and Affiliations

  1. Institute of Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Julia Schipke & Christian Mühlfeld

  2. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), 30625, Hannover, Germany

    Christian Mühlfeld

  3. Institute of Physiology, University of Würzburg, 97070, Würzburg, Germany

    Konstanze Roloff & Michaela Kuhn

  4. Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Julia Schipke & Christian Mühlfeld

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  1. Julia Schipke
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Correspondence to Julia Schipke.

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Schipke, J., Roloff, K., Kuhn, M. et al. Systemic, but not cardiomyocyte-specific, deletion of the natriuretic peptide receptor guanylyl cyclase A increases cardiomyocyte number in neonatal mice. Histochem Cell Biol 144, 365–375 (2015). https://doi.org/10.1007/s00418-015-1337-z

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