Abstract 11236: PMCA4 Ablation in Cardiac Fibroblasts Modulates Cardiomyocyte Hypertrophy via a Paracrine Effect
Identification of novel regulators of cardiac hypertrophy is key in understanding the mechanisms of heart failure. The plasma membrane calcium ATPase 4 (PMCA4) is a ubiquitously expressed Ca2+ pump that is involved in molecular signalling in the heart. Here we investigated a novel role of PMCA4 in cardiac fibroblasts in controlling myocardial hypertrophy.
We subjected mice with a global knockout of PMCA4 (PMCA4-/-) to transverse aortic constriction (TAC) for 5 weeks. PMCA4-/- mice exhibited a significantly reduced hypertrophic response compared with wild type (WT) mice. This was accompanied by less fibrosis and a lower expression of hypertrophic marker BNP. However, cardiomyocyte specific knockout of PMCA4 did not show any protective effect following 5 weeks TAC prompting us to hypothesise that the protective effect might be due to PMCA4 ablation in fibroblasts. Microarray analysis revealed a ~100 folds upregulation of secreted frizzled-related protein 2 (sFRP2) in PMCA4-/- fibroblasts, which was confirmed by real time PCR. sFRP2 is a potent inhibitor of the Wnt/β-catenin pathway. We then co-cultured WT cardiomyocytes with either PMCA4-/- or WT fibroblasts. In response to phenylephrine stimulation cardiomyocytes cultured with PMCA4-/- fibroblasts displayed 88% less hypertrophy than those cultured with WT fibroblasts (P<0.01). Addition of anti-sFRP2 antibody abolished the anti-hypertrophic effect of PMCA4-/- fibroblasts, suggesting that the phenotype might be due to the paracrine effect of sFRP2. Mechanistically, PMCA4-/- fibroblasts showed a significant elevation in NFκB activity, a transcription factor regulating sFRP2 expression. Inhibition of NFκB activity significantly reduced the expression of sFRP2 in PMCA4-/- fibroblasts to the level comparable with WT expression.
In conclusion, our data provides new evidence that PMCA4-mediated signaling in cardiac fibroblasts plays a key role in controlling cardiac hypertrophy. Cardiac fibroblasts lacking PMCA4 produces higher levels of sFRP2 which inhibits the hypertrophic response in the neighbouring cardiomyocytes. Finally, PMCA4 might be a target for the treatment of cardiac hypertrophy in the future.
- © 2013 by American Heart Association, Inc.