Key result
Genetic ablation or pharmacological inhibition of PMCA4 in cardiac fibroblasts attenuates pressure overload-induced cardiomyocyte hypertrophy by increasing the secretion of sFRP2.
Why the study?
Does PMCA4 inhibition prevent cardiac hypertrophy in preclinical models of pressure overload?
Does PMCA4 inhibition prevent cardiac hypertrophy in preclinical models of pressure overload?
PMCA4 inhibition in cardiac fibroblasts attenuates cardiomyocyte hypertrophy via increased sFRP2 secretion, suggesting a potential therapeutic target for pathological cardiac hypertrophy.
PMCA4 inhibition merits further preclinical testing as a hypertrophy target; leaves open translation from this animal model to patients.
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.
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Mohamed et al. (2016) studied Cardiac hypertrophy. PMCA4 genetic ablation or pharmacological inhibition (aurintricarboxylic acid) vs. Wild type or vehicle was evaluated on Hypertrophic response to pressure overload. Genetic ablation or pharmacological inhibition of PMCA4 in cardiac fibroblasts attenuates pressure overload-induced cardiomyocyte hypertrophy by increasing the secretion of sFRP2.
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