The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy

Tamer M. A. Mohamed, Riham Abou-Leisa, Nicholas Stafford, Arfa Maqsood, Min Zi, Sukhpal Prehar, Florence Baudoin-Stanley, Xin Wang, Ludwig Neyses, Elizabeth J. Cartwright and Delvac Oceandy ()
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Tamer M. A. Mohamed: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Riham Abou-Leisa: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Nicholas Stafford: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Arfa Maqsood: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Min Zi: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Sukhpal Prehar: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Florence Baudoin-Stanley: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Xin Wang: Faculty of Life Sciences, University of Manchester
Ludwig Neyses: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Elizabeth J. Cartwright: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK
Delvac Oceandy: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract The heart responds to pathological overload through myocyte hypertrophy. Here we show that this response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4). Pmca4 deletion in mice, both systemically and specifically in fibroblasts, reduces the hypertrophic response to pressure overload; however, knocking out Pmca4 specifically in cardiomyocytes does not produce this effect. Mechanistically, cardiac fibroblasts lacking PMCA4 produce higher levels of secreted frizzled related protein 2 (sFRP2), which inhibits the hypertrophic response in neighbouring cardiomyocytes. Furthermore, we show that treatment with the PMCA4 inhibitor aurintricarboxylic acid (ATA) inhibits and reverses cardiac hypertrophy induced by pressure overload in mice. Our results reveal that PMCA4 regulates the development of cardiac hypertrophy and provide proof of principle for a therapeutic approach to treat this condition.

Date: 2016
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DOI: 10.1038/ncomms11074

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