title: The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy.
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.
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.|J David Gladstone Research Institutes, San Francisco, California 94158, USA.|Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Tamer M A
authors.identifier: http://orcid.org/0000-0002-8435-808X
authors.initials: TMA
authors.lastname: Mohamed
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Riham
authors.initials: R
authors.lastname: Abou-Leisa
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stafford
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Arfa
authors.initials: A
authors.lastname: Maqsood
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Zi
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Sukhpal
authors.initials: S
authors.lastname: Prehar
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Florence
authors.initials: F
authors.lastname: Baudoin-Stanley
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
authors.forename: Delvac
authors.initials: D
authors.lastname: Oceandy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000473:pathology; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D006332:Cardiomegaly / Q000150:complications / Q000473:pathology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D003251:Constriction, Pathologic; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D017353:Gene Deletion; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011312:Pressure; D015398:Signal Transduction / Q000187:drug effects; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D001312:Aurintricarboxylic Acid; D000252:Calcium-Transporting ATPases; D017077:Culture Media, Conditioned; D008565:Membrane Proteins; C000589038:ATP2B4 protein, mouse; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins