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

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.

• Authors: H Diedrichs, C Mei, K F Frank, B Boelck, R H G Schwinger
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 82 Issue 10 Pg. 688-95 (Oct 2004) ISSN: 0946-2716 [Print] Germany
• PMID: 15322704 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• GATA4 Transcription Factor
• NFATC Transcription Factors
• Nuclear Proteins
• RNA, Messenger
• Transcription Factors
• Calcineurin
• Renin

Topics

• Animals
• Animals, Genetically Modified
• Blotting, Western
• Calcineurin (genetics, metabolism, physiology)
• Cardiomegaly (genetics, metabolism, physiopathology)
• DNA-Binding Proteins (analysis, genetics, metabolism)
• GATA4 Transcription Factor
• Gene Expression Regulation
• Male
• Mice
• Myocardium (metabolism)
• NFATC Transcription Factors
• Nuclear Proteins (analysis)
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Renin (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (analysis)