Abstract 11340: The Plasma Membrane Calcium ATPase 4 Signaling in Cardiac Fibroblasts Mediates Cardiomyocyte Hypertrophy (Best of Basic Science Abstract)
Plasma membrane calcium ATPase 4 (PMCA4) is a ubiquitously expressed Ca2+ pump that is important in mediating molecular signaling in the heart. Here we show a novel role of PMCA4 in cardiac fibroblasts in controlling cardiac hypertrophy.
We generated three PMCA4 knockout mouse strains: i) PMCA4 global knockout (PMCA4-/-); ii) PMCA4 cardiomyocyte-specific knockout (PMCA4cko); iii) PMCA4 fibroblast-specific knockout (PMCA4fko). Following transverse aortic constriction (TAC) for 5 weeks, PMCA4-/- and PMCA4fko mice displayed a significantly reduced hypertrophy compared to control mice. In contrast, the PMCA4 cardiac specific knockout (PMCA4cko) mice did not show any protective effect following TAC, prompting us to hypothesise that the protective effect might be due to PMCA4 ablation in fibroblasts. Microarray analysis revealed a ~100 fold upregulation of secreted frizzled-related protein 2 (sFRP2) in PMCA4-/- fibroblasts, which was further confirmed by qRT-PCR and Western blot. sFRP2 is a potent inhibitor of the Wnt/β-catenin pathway. We then cultured wild type (WT) cardiomyocytes with conditioned medium from either PMCA4-/- or WT fibroblasts. In response to phenylephrine stimulation, cardiomyocytes cultured in PMCA4-/- fibroblast–conditioned medium displayed 88% less hypertrophy than those cultured in WT fibroblast–conditioned medium (P<0.01). Mechanistically, PMCA4-/- fibroblasts showed a significant elevation in NFκB activity, a transcription factor that regulates sFRP2 expression. Inhibition of NFκB activity significantly reduced the sFRP2 expression in PMCA4-/- fibroblasts to a level comparable to WT expression. A chemical library screen identified a novel PMCA4 inhibitor, aurintricarboxylic acid (ATA). ATA treatment enhanced sFRP2 expression in the mouse heart. Importantly, ATA inhibited and reversed TAC-induced cardiac hypertrophy in mice, demonstrating its efficacy in both preventive and therapeutic strategies.
In conclusion, PMCA4-mediated signaling in cardiac fibroblasts plays a key role in controlling cardiac hypertrophy. Cardiac fibroblasts lacking PMCA4 produce higher levels of sFRP2, which protects the neighbouring cardiomyocytes. Finally, PMCA4 is a potential target for cardiac hypertrophy treatment.
Author Disclosures: T.M. Mohamed: None. R. AbouLeisa: None. N. Stafford: None. M. Zi: None. S. Prehar: None. F. Baudoin: None. E. Cartwright: None. L. Neyses: None. D. Oceandy: None.
- © 2015 by American Heart Association, Inc.