TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy
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...
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.00523/full |
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| author | Caroline Sunggip Caroline Sunggip Kakeru Shimoda Kakeru Shimoda Sayaka Oda Sayaka Oda Tomohiro Tanaka Kazuhiro Nishiyama Supachoke Mangmool Akiyuki Nishimura Akiyuki Nishimura Takuro Numaga-Tomita Takuro Numaga-Tomita Motohiro Nishida Motohiro Nishida Motohiro Nishida |
| author_facet | Caroline Sunggip Caroline Sunggip Kakeru Shimoda Kakeru Shimoda Sayaka Oda Sayaka Oda Tomohiro Tanaka Kazuhiro Nishiyama Supachoke Mangmool Akiyuki Nishimura Akiyuki Nishimura Takuro Numaga-Tomita Takuro Numaga-Tomita Motohiro Nishida Motohiro Nishida Motohiro Nishida |
| author_sort | Caroline Sunggip |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T13:14:14Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T13:14:14Z |
| publishDate | 2018-05-01 |
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| spelling | doaj.art-a4753e6a469d4c0698a6960a9822ea142022-12-22T02:45:31ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-05-01910.3389/fphar.2018.00523353950TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte HypertrophyCaroline Sunggip0Caroline Sunggip1Kakeru Shimoda2Kakeru Shimoda3Sayaka Oda4Sayaka Oda5Tomohiro Tanaka6Kazuhiro Nishiyama7Supachoke Mangmool8Akiyuki Nishimura9Akiyuki Nishimura10Takuro Numaga-Tomita11Takuro Numaga-Tomita12Motohiro Nishida13Motohiro Nishida14Motohiro Nishida15Division of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Biomedical Science and Therapeutic, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, MalaysiaDivision of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, JapanDivision of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, JapanDivision of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, JapanDepartment of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, ThailandDivision of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, JapanDivision of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, JapanDivision of Cardiocirculatory Signaling, Creative Research Group on Cardiocirculatory Dynamism, Exploratory Research Center on Life and Living Systems, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, JapanDepartment of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, JapanCardiac 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.https://www.frontiersin.org/article/10.3389/fphar.2018.00523/fullcardiac hypertrophyTRPC cation channelsnitric oxide synthaseNFATadenosine triphosphate |
| spellingShingle | Caroline Sunggip Caroline Sunggip Kakeru Shimoda Kakeru Shimoda Sayaka Oda Sayaka Oda Tomohiro Tanaka Kazuhiro Nishiyama Supachoke Mangmool Akiyuki Nishimura Akiyuki Nishimura Takuro Numaga-Tomita Takuro Numaga-Tomita Motohiro Nishida Motohiro Nishida Motohiro Nishida TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy Frontiers in Pharmacology cardiac hypertrophy TRPC cation channels nitric oxide synthase NFAT adenosine triphosphate |
| title | TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy |
| title_full | TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy |
| title_fullStr | TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy |
| title_full_unstemmed | TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy |
| title_short | TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy |
| title_sort | trpc5 enos axis negatively regulates atp induced cardiomyocyte hypertrophy |
| topic | cardiac hypertrophy TRPC cation channels nitric oxide synthase NFAT adenosine triphosphate |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.00523/full |
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