TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy

Caroline Sunggip, Kakeru Shimoda, Sayaka Oda, Tomohiro Tanaka, Kazuhiro Nishiyama, Supachoke Mangmool, Akiyuki Nishimura, Takuro Numaga-Tomita, Motohiro Nishida

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number523
JournalFrontiers in Pharmacology
Volume9
Issue numberMAY
DOIs
Publication statusPublished - May 22 2018

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Cardiac Myocytes
Hypertrophy
Adenosine Triphosphate
NFATC Transcription Factors
Cyclic GMP-Dependent Protein Kinases
Nitric Oxide
Endothelin-1
Nitric Oxide Synthase
Angiotensin II
Ligands
Inositol 1,4,5-Trisphosphate Receptors
Purinergic Receptors
Inositol 1,4,5-Trisphosphate
Calcineurin
Brain Natriuretic Peptide
Diglycerides
Cardiomegaly
Causality
Nucleotides
Heart Failure

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy. / Sunggip, Caroline; Shimoda, Kakeru; Oda, Sayaka; Tanaka, Tomohiro; Nishiyama, Kazuhiro; Mangmool, Supachoke; Nishimura, Akiyuki; Numaga-Tomita, Takuro; Nishida, Motohiro.

In: Frontiers in Pharmacology, Vol. 9, No. MAY, 523, 22.05.2018.

Research output: Contribution to journalArticle

Sunggip, C, Shimoda, K, Oda, S, Tanaka, T, Nishiyama, K, Mangmool, S, Nishimura, A, Numaga-Tomita, T & Nishida, M 2018, 'TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy', Frontiers in Pharmacology, vol. 9, no. MAY, 523. https://doi.org/10.3389/fphar.2018.00523
Sunggip C, Shimoda K, Oda S, Tanaka T, Nishiyama K, Mangmool S et al. TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy. Frontiers in Pharmacology. 2018 May 22;9(MAY). 523. https://doi.org/10.3389/fphar.2018.00523
Sunggip, Caroline ; Shimoda, Kakeru ; Oda, Sayaka ; Tanaka, Tomohiro ; Nishiyama, Kazuhiro ; Mangmool, Supachoke ; Nishimura, Akiyuki ; Numaga-Tomita, Takuro ; Nishida, Motohiro. / TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy. In: Frontiers in Pharmacology. 2018 ; Vol. 9, No. MAY.
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