Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations in human airway smooth muscle cells

Akemi Mori, Satoru Ito, Masataka Morioka, Hiromichi Aso, Masashi Kondo, Masahiro Sokabe, Yoshinori Hasegawa

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Increased airway smooth muscle mass due to cell proliferation contributes to airway hyper-responsiveness and remodeling in patients with asthma. Prostaglandin E2 (PGE2) inhibits proliferation of airway smooth muscle cells, but the role of prostanoid EP receptor subtypes in mechanisms involved has not been fully elucidated yet. We investigated the effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations ([Ca2+]i) in human airway smooth muscle cells. Cell numbers were assessed by mitochondria-dependent reduction of 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5- tetrazolio]-1, 3-benzene disulfonate to formazan (WST-1 assay). RT-PCR data showed that human airway smooth muscle cells express EP2, EP3, and EP4 but not EP1 receptor mRNA. PGE2 (1 nM-1 μM) inhibited cell proliferation induced by 5% fetal bovine serum (FBS) in a concentration-dependent manner. (16S)-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17, 17-trimethylene-19, 20-didehydro PGE2 sodium salt (ONO-AE1-259-01; EP2 receptor agonist) and 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia PGE2 (ONO-AE1-329; EP4 receptor agonist) inhibited the 5% FBS-induced cell proliferation. ONO-AE1-259-01 and ONO-AE1-329 also significantly increased the cytosolic cAMP levels. In contrast, 11,15-O-dimethyl PGE2 (ONO-AE-248; EP3 receptor agonist) elicited an oscillatory increase in [Ca 2+]i but did not affect the cell growth or cAMP levels. [(17S)-2,5-ethano-6-oxo-17,20-dimethyl PGE1] (ONO-DI-004; EP1 receptor agonist) did not affect cell growth, cAMP levels, or [Ca 2+]i. In conclusion, PGE2 inhibits FBS-induced cell proliferation mostly via EP2 and EP4 receptor activation and subsequent cAMP elevation. The EP3 receptor agonist causes an increase in [Ca 2+]i without affecting cell growth. There is no functional expression of the EP1 receptor. Research on prostanoid EP receptors may lead to novel therapeutic strategies for treatment of asthma.

Original languageEnglish
Pages (from-to)72-78
Number of pages7
JournalEuropean Journal of Pharmacology
Volume659
Issue number1
DOIs
Publication statusPublished - 20-05-2011
Externally publishedYes

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Dinoprostone
Prostaglandins
Smooth Muscle Myocytes
Cell Proliferation
Respiratory Hypersensitivity
Asthma
Growth
Serum
Formazans
Alprostadil
Smooth Muscle
Mitochondria
Salts
Cell Count
Sodium
Polymerase Chain Reaction
Messenger RNA
Research
11,15-O-dimethylprostaglandin E2
ONO-AE1-329

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Medicine(all)

Cite this

Mori, Akemi ; Ito, Satoru ; Morioka, Masataka ; Aso, Hiromichi ; Kondo, Masashi ; Sokabe, Masahiro ; Hasegawa, Yoshinori. / Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations in human airway smooth muscle cells. In: European Journal of Pharmacology. 2011 ; Vol. 659, No. 1. pp. 72-78.
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abstract = "Increased airway smooth muscle mass due to cell proliferation contributes to airway hyper-responsiveness and remodeling in patients with asthma. Prostaglandin E2 (PGE2) inhibits proliferation of airway smooth muscle cells, but the role of prostanoid EP receptor subtypes in mechanisms involved has not been fully elucidated yet. We investigated the effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations ([Ca2+]i) in human airway smooth muscle cells. Cell numbers were assessed by mitochondria-dependent reduction of 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5- tetrazolio]-1, 3-benzene disulfonate to formazan (WST-1 assay). RT-PCR data showed that human airway smooth muscle cells express EP2, EP3, and EP4 but not EP1 receptor mRNA. PGE2 (1 nM-1 μM) inhibited cell proliferation induced by 5{\%} fetal bovine serum (FBS) in a concentration-dependent manner. (16S)-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17, 17-trimethylene-19, 20-didehydro PGE2 sodium salt (ONO-AE1-259-01; EP2 receptor agonist) and 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia PGE2 (ONO-AE1-329; EP4 receptor agonist) inhibited the 5{\%} FBS-induced cell proliferation. ONO-AE1-259-01 and ONO-AE1-329 also significantly increased the cytosolic cAMP levels. In contrast, 11,15-O-dimethyl PGE2 (ONO-AE-248; EP3 receptor agonist) elicited an oscillatory increase in [Ca 2+]i but did not affect the cell growth or cAMP levels. [(17S)-2,5-ethano-6-oxo-17,20-dimethyl PGE1] (ONO-DI-004; EP1 receptor agonist) did not affect cell growth, cAMP levels, or [Ca 2+]i. In conclusion, PGE2 inhibits FBS-induced cell proliferation mostly via EP2 and EP4 receptor activation and subsequent cAMP elevation. The EP3 receptor agonist causes an increase in [Ca 2+]i without affecting cell growth. There is no functional expression of the EP1 receptor. Research on prostanoid EP receptors may lead to novel therapeutic strategies for treatment of asthma.",
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Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations in human airway smooth muscle cells. / Mori, Akemi; Ito, Satoru; Morioka, Masataka; Aso, Hiromichi; Kondo, Masashi; Sokabe, Masahiro; Hasegawa, Yoshinori.

In: European Journal of Pharmacology, Vol. 659, No. 1, 20.05.2011, p. 72-78.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations in human airway smooth muscle cells

AU - Mori, Akemi

AU - Ito, Satoru

AU - Morioka, Masataka

AU - Aso, Hiromichi

AU - Kondo, Masashi

AU - Sokabe, Masahiro

AU - Hasegawa, Yoshinori

PY - 2011/5/20

Y1 - 2011/5/20

N2 - Increased airway smooth muscle mass due to cell proliferation contributes to airway hyper-responsiveness and remodeling in patients with asthma. Prostaglandin E2 (PGE2) inhibits proliferation of airway smooth muscle cells, but the role of prostanoid EP receptor subtypes in mechanisms involved has not been fully elucidated yet. We investigated the effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations ([Ca2+]i) in human airway smooth muscle cells. Cell numbers were assessed by mitochondria-dependent reduction of 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5- tetrazolio]-1, 3-benzene disulfonate to formazan (WST-1 assay). RT-PCR data showed that human airway smooth muscle cells express EP2, EP3, and EP4 but not EP1 receptor mRNA. PGE2 (1 nM-1 μM) inhibited cell proliferation induced by 5% fetal bovine serum (FBS) in a concentration-dependent manner. (16S)-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17, 17-trimethylene-19, 20-didehydro PGE2 sodium salt (ONO-AE1-259-01; EP2 receptor agonist) and 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia PGE2 (ONO-AE1-329; EP4 receptor agonist) inhibited the 5% FBS-induced cell proliferation. ONO-AE1-259-01 and ONO-AE1-329 also significantly increased the cytosolic cAMP levels. In contrast, 11,15-O-dimethyl PGE2 (ONO-AE-248; EP3 receptor agonist) elicited an oscillatory increase in [Ca 2+]i but did not affect the cell growth or cAMP levels. [(17S)-2,5-ethano-6-oxo-17,20-dimethyl PGE1] (ONO-DI-004; EP1 receptor agonist) did not affect cell growth, cAMP levels, or [Ca 2+]i. In conclusion, PGE2 inhibits FBS-induced cell proliferation mostly via EP2 and EP4 receptor activation and subsequent cAMP elevation. The EP3 receptor agonist causes an increase in [Ca 2+]i without affecting cell growth. There is no functional expression of the EP1 receptor. Research on prostanoid EP receptors may lead to novel therapeutic strategies for treatment of asthma.

AB - Increased airway smooth muscle mass due to cell proliferation contributes to airway hyper-responsiveness and remodeling in patients with asthma. Prostaglandin E2 (PGE2) inhibits proliferation of airway smooth muscle cells, but the role of prostanoid EP receptor subtypes in mechanisms involved has not been fully elucidated yet. We investigated the effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca2+ concentrations ([Ca2+]i) in human airway smooth muscle cells. Cell numbers were assessed by mitochondria-dependent reduction of 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5- tetrazolio]-1, 3-benzene disulfonate to formazan (WST-1 assay). RT-PCR data showed that human airway smooth muscle cells express EP2, EP3, and EP4 but not EP1 receptor mRNA. PGE2 (1 nM-1 μM) inhibited cell proliferation induced by 5% fetal bovine serum (FBS) in a concentration-dependent manner. (16S)-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17, 17-trimethylene-19, 20-didehydro PGE2 sodium salt (ONO-AE1-259-01; EP2 receptor agonist) and 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia PGE2 (ONO-AE1-329; EP4 receptor agonist) inhibited the 5% FBS-induced cell proliferation. ONO-AE1-259-01 and ONO-AE1-329 also significantly increased the cytosolic cAMP levels. In contrast, 11,15-O-dimethyl PGE2 (ONO-AE-248; EP3 receptor agonist) elicited an oscillatory increase in [Ca 2+]i but did not affect the cell growth or cAMP levels. [(17S)-2,5-ethano-6-oxo-17,20-dimethyl PGE1] (ONO-DI-004; EP1 receptor agonist) did not affect cell growth, cAMP levels, or [Ca 2+]i. In conclusion, PGE2 inhibits FBS-induced cell proliferation mostly via EP2 and EP4 receptor activation and subsequent cAMP elevation. The EP3 receptor agonist causes an increase in [Ca 2+]i without affecting cell growth. There is no functional expression of the EP1 receptor. Research on prostanoid EP receptors may lead to novel therapeutic strategies for treatment of asthma.

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