A novel role of sesamol in inhibiting NF-B-mediated signaling in platelet activation

Chao Chien Chang, Wan-Jung Lu, Eng Thiam Ong, Cheng-Wen Chiang, Song-Chow Lin, Shih Yi Huang, Joen Rong Sheu

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-B, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-B-mediated platelet function. Methods. Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study. Results: NF-B signaling events, including IKK phosphorylation, IB degradation, and p65 phosphorylation, were markedly activated by collagen (1 g/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5∼25 M). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 M)-mediated inhibitory effects of IKK phosphorylation, IB degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IB degradation. Moreover, BAY11-7082, an NF-B inhibitor, abolished IB degradation, phospholipase C (PLC)2 phosphorylation, protein kinase C (PKC) activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization. Conclusions: Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-B-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-B interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.

Original languageEnglish
Article number93
JournalJournal of Biomedical Science
Volume18
Issue number1
DOIs
Publication statusPublished - 2011

Fingerprint

Platelet Activation
Platelets
Chemical activation
Platelet Aggregation
Phosphorylation
Blood Platelets
Collagen
Type C Phospholipases
Cyclic AMP-Dependent Protein Kinases
Protein Kinase C
Agglomeration
Degradation
Fura-2
Guanylate Cyclase
Platelet Aggregation Inhibitors
Protein Kinase Inhibitors
sesamol
Hemostasis
Immunoblotting
Cyclic AMP

Keywords

  • IB
  • IKK
  • intracellular Ca
  • platelet activation
  • protein kinase A
  • sesamol

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Pharmacology (medical)

Cite this

A novel role of sesamol in inhibiting NF-B-mediated signaling in platelet activation. / Chang, Chao Chien; Lu, Wan-Jung; Ong, Eng Thiam; Chiang, Cheng-Wen; Lin, Song-Chow; Huang, Shih Yi; Sheu, Joen Rong.

In: Journal of Biomedical Science, Vol. 18, No. 1, 93, 2011.

Research output: Contribution to journalArticle

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abstract = "Background: Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-B, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-B-mediated platelet function. Methods. Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study. Results: NF-B signaling events, including IKK phosphorylation, IB degradation, and p65 phosphorylation, were markedly activated by collagen (1 g/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5∼25 M). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 M)-mediated inhibitory effects of IKK phosphorylation, IB degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IB degradation. Moreover, BAY11-7082, an NF-B inhibitor, abolished IB degradation, phospholipase C (PLC)2 phosphorylation, protein kinase C (PKC) activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization. Conclusions: Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-B-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-B interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.",
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T1 - A novel role of sesamol in inhibiting NF-B-mediated signaling in platelet activation

AU - Chang, Chao Chien

AU - Lu, Wan-Jung

AU - Ong, Eng Thiam

AU - Chiang, Cheng-Wen

AU - Lin, Song-Chow

AU - Huang, Shih Yi

AU - Sheu, Joen Rong

PY - 2011

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N2 - Background: Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-B, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-B-mediated platelet function. Methods. Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study. Results: NF-B signaling events, including IKK phosphorylation, IB degradation, and p65 phosphorylation, were markedly activated by collagen (1 g/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5∼25 M). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 M)-mediated inhibitory effects of IKK phosphorylation, IB degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IB degradation. Moreover, BAY11-7082, an NF-B inhibitor, abolished IB degradation, phospholipase C (PLC)2 phosphorylation, protein kinase C (PKC) activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization. Conclusions: Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-B-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-B interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.

AB - Background: Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-B, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-B-mediated platelet function. Methods. Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study. Results: NF-B signaling events, including IKK phosphorylation, IB degradation, and p65 phosphorylation, were markedly activated by collagen (1 g/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5∼25 M). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 M)-mediated inhibitory effects of IKK phosphorylation, IB degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IB degradation. Moreover, BAY11-7082, an NF-B inhibitor, abolished IB degradation, phospholipase C (PLC)2 phosphorylation, protein kinase C (PKC) activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization. Conclusions: Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-B-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-B interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.

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KW - protein kinase A

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