- 作者: Chang CC, Lu WJ, Ong ET, Chiang CW, Lin SC, Huang SY and Sheu JR
- 作者服務機構: Graduate Institute of Clinical Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
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-κB, that may exert non-genomic
functions in platelet activation. Therefore, we further investigated the inhibitory roles
of sesamol in NF-κB-mediated platelet function.
Methods: Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting
analysis were used in this study.
Results: NF-κB signaling events, including IKKβ phosphorylation, IκBα degradation,
and p65 phosphorylation, were markedly activated by collagen (1 μg/ml) in washed
human platelets, and these signaling events were attenuated by sesamol (2.5~25 μM).
Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate
cyclase, respectively, strongly reversed the sesamol (25 μΜ)-mediated inhibitory
effects of IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation
stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed
sesamol-mediated inhibition of IκBα degradation. Moreover, BAY11-7082, an NF-κB
inhibitor, abolished IκBα degradation, phospholipase C (PLC)γ2 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-κB-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-κB 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. - 中文關鍵字: --
- 英文關鍵字: IκBα; IKK; intracellular Ca2+; protein kinase A; platelet activation; sesamol