Abstract
Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca2+-dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5′-triphosphate (ATP), is also known as most potent Ca2+-mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca2+ signaling requires inositol 1,4,5-trisphosphate (IP3) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca2+/NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP3-mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation.
Highlights
Myocardial hypertrophy is the major predisposing factor for heart failure, arrhythmia and sudden death (Levy et al, 1990)
We demonstrate that adenosine triphosphate (ATP) induces IP3-dependent Ca2+ signaling and nitric oxide (NO) production in neonatal rat cardiomyocytes (NRCMs), as well as functional coupling between IP3-responsive TRPC5 channel and endothelial NO synthase (NOS) contributes to negative regulation of hypertrophic signaling induced by ATP stimulation
We demonstrated that ATP-induced increases in [Ca2+]i and nuclear factor of activated T cell (NFAT) activity are not sufficient to induce hypertrophic responses in NRCMs
Summary
Myocardial hypertrophy is the major predisposing factor for heart failure, arrhythmia and sudden death (Levy et al, 1990). Neurohumoral factors are known to stimulate G protein-coupled receptor (GPCR), leading to activation of phospholipase C (PLC), which in turn generates diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) that are responsible for sustained increase in intracellular Ca2+ concentration ([Ca2+]i) (Berridge et al, 2003). The sustained [Ca2+]i increase induces pathological myocardial hypertrophy through activation of calcineurinnuclear factor of activated T cell (NFAT) signaling pathway (Molkentin et al, 1998; Berridge et al, 2003; Heineke and Molkentin, 2006). Studies have consistently shown that DAG-activated TRPC3 and TRPC6 (TRPC3/6) channels function as an important mediator of GPCR-stimulated Ca2+ signaling pathway that may participate in pathological cardiac hypertrophy (Kuwahara et al, 2006; Nakayama et al, 2006; Onohara et al, 2006). Inhibition of TRPC3/6 channels have been reported to attenuate heart failure through suppressing myocardial hypertrophy and interstitial fibrosis (Kiyonaka et al, 2009; Kitajima et al, 2011, 2016; Numaga-Tomita et al, 2016)
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