TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy

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.

TRPC Channels in Cardiac Plasticity

“…The suppression of TRPC5 results in a reduction of ATP-induced NO production, thus promoting hypertrophic responses in cardiomyocytes. These results suggest that TRPC channels also function as negative regulators of cardiac remodeling [91].…”

“…Moreover, reported expression of TRPC5 in the heart and its change during heart failure vary among studies [88][89][90]. Recently we demonstrated that TRPC5 has an anti-hypertrophic effect in cardiomyocytes [91]. Based on the dogma mentioned above, the CaN/NFAT pathway is critical for cardiac hypertrophy.…”

“…Based on the dogma mentioned above, the CaN/NFAT pathway is critical for cardiac hypertrophy. However, purinergic receptor activation by ATP dose not induce hypertrophy, even with a clear increase of CaN/NFAT activity [91]. The reason ATP cannot induce hypertrophy is nitric oxide (NO) production, which is not evoked by other hypertrophic stimulation of AngII or endothelin.…”

Effect of SKF‑96365 on cardiomyocyte hypertrophy induced by angiotensin II

“…Therefore, TrPc channels have been regarded as drug therapeutic targets for cardiac hypertrophy (27). a number of previous studies have demonstrated that the expression of TrPc1, TrPc5, TrPc6 and TrPc7 are markedly upregulated in cardiac hypertrophy, and accumulating evidence has demonstrated that TrPc channels are related to cardiac hypertrophy (28)(29)(30)(31). Whether TrPc channels have a role in the development of cardiomyocyte hypertrophy, and whether TrPc channels are involved in the process of cardiomyocyte hypertrophy induced by ang ii remain unclear.…”

TRPC channels: Dysregulation and Ca²⁺ Mishandling In Ischemic Heart Disease

“…Peer-reviewed version available at Cells 2020, 9, 173; doi:10.3390/cells9010173 from sinoatrial node, atrial or ventricular heart [14,[16][17][18][19]. In human cardiac tissues and/or neonatal rat cardiomyocytes mRNA of TRPC5 [20,21] and TRPC6 [22] were detected. In animal model, the expression of TRPC1/3-7 have been confirmed in adult rat and mouse ventricle and atrial cardiac myocytes either at mRNA or protein levels [13,23,24].…”