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Calcineurin independent development of myocardial hypertrophy in transgenic rats overexpressing the mouse renin gene, TGR(mREN2)27

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Abstract

Myocardial hypertrophy is an independent risk factor for development of heart failure. The intracellular calcium homeostasis is altered in myocardial hypertrophy, and recent studies in animal models have confirmed an interaction between the Ca2+/calmodulin-dependent calcineurin signaling cascade and development of cardiac hypertrophy. There is evidence for the involvement of various pathways in development of hypertrophy. A transgenic rat model overexpressing the mouse renin gene, TGR(mREN2)27 has been shown to progress profound cardiac hypertrophy, possibly due to a monogenetic disorder. However, the exact mode of action is not known. To study a possible involvement of calcineurin and its downstream pathway in development of cardiac hypertrophy in this transgenic rat model we measured the protein expression of marker proteins of the calcineurin cascade (calcineurin, NFAT-3, GATA-4) and calcineurin phosphatase activity and GATA-4 DNA binding in TGR (n=10) compared to age-matched Sprague-Dawley rats (n=10). In our study there was no significant difference in calcineurin activity between the transgenic hearts and the hearts of Sprague-Dawley rats. Furthermore, we found neither an increase in protein expression of calcineurin B nor a rise in nuclear translocated NFAT-3 DU. Interestingly, the protein expression of GATA-4 and its DNA binding activity were significantly higher in hypertrophied myocardium than in control hearts. In transgenic rats overexpressing the mouse renin gene and thereby developing pronounced cardiac hypertrophy [TGR(mREN2)27] we thus found no activation of calcineurin or its downstream pathway. However, the expression of the transcriptional factor GATA-4 and its DNA binding activity were significantly increased in hearts of transgenic rats. Thus GATA-4 seems to be a marker of hypertrophy independently of calcineurin activation, possibly activated by various pathways.

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Abbreviations

DU :

Densitometric units

ERK :

Extracellular signal regulated kinase

MAP :

Mitogen-activated protein

NFAT :

Nuclear factor activated T cell

PCR :

Polymerase chain reaction

SPDR :

Sprague-Dawley rat

TGR :

TGR(mREN2)27 mouse

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Acknowledgements

This study was supported by the Ernst und Berta Grimmke-Stiftung (to H.D. and R.H.G.S). We thank Katja Rösler for excellent technical assistance. The mouse renin gene overexpressing rats were generously provided by Prof. Martin Paul, Freie Universität Berlin.

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Authors and Affiliations

  1. Laboratory for Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924, Cologne, Germany

    H. Diedrichs, C. Mei, K. F. Frank, B. Boelck & R. H. G. Schwinger

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  1. H. Diedrichs
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  2. C. Mei
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  3. K. F. Frank
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  4. B. Boelck
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  5. R. H. G. Schwinger
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Correspondence to H. Diedrichs.

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H. Diedrichs and C. Mei contributed equally to this work

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Diedrichs, H., Mei, C., Frank, K.F. et al. Calcineurin independent development of myocardial hypertrophy in transgenic rats overexpressing the mouse renin gene, TGR(mREN2)27. J Mol Med 82, 688–695 (2004). https://doi.org/10.1007/s00109-004-0581-9

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