Abstract
Platelets are major players in the occurrence of cardiovascular diseases. Auraptene is the most abundant coumarin derivative from plants, and it has been demonstrated to possess a potent capacity to inhibit platelet activation. Although platelets are anucleated cells, they also express the transcription factor, nuclear factor-κB (NF-κB), that may exert non-genomic functions in platelet activation. In the current study, we further investigated the inhibitory roles of auraptene in NF-κB-mediated signal events in platelets. MG-132 (an inhibitor of proteasome) and BAY11-7082 (an inhibitor of IκB kinase; IKK), obviously inhibited platelet aggregation; however, BAY11-7082 exhibited more potent activity than MG-132 in this reaction. The existence of NF-κB (p65) in platelets was observed by confocal microscopy, and auraptene attenuated NF-κB activation such as IκBα and p65 phosphorylation and reversed IκBα degradation in collagen-activated platelets. To investigate cellular signaling events between PLCγ2-PKC and NF-κB, we found that BAY11-7082 abolished PLCγ2-PKC activation; nevertheless, neither U73122 nor Ro31-8220 had effect on NF-κB activation. Furthermore, both auraptene and BAY11-7082 significantly diminished HO• formation in activated platelets. For in vivo study, auraptene prolonged the occlusion time of platelet plug in mice. In conclusion, we propose a novel inhibitory pathway of NF-κB-mediated PLCγ2-PKC activation by auraptene in human platelets, and further supported that auraptene possesses potent activity for thromboembolic diseases.
Highlights
Cardiovascular diseases (CVDs) are the largest cause of death globally
In our previous report [14], we found that auraptene markedly inhibited collagen (1 μg/mL)-stimulated human platelet activation, and it IC50 was approximated at 35 μM
We suggested the mechanisms of auraptene in platelet activation may be through interference with the phosphorylation of PLCγ2-PKC cascade stimulated by collagen
Summary
Cardiovascular diseases (CVDs) are the largest cause of death globally. CVDs are often caused by thrombotic events such as coronary heart disease. Platelets are major players in the occurrence of CVDs since they are involved in various thrombo-inflammatory diseases, atherosclerosis and its progression to atherothrombosis in acute coronary syndrome (ACS) patients [1]. The inside-out signaling of the integrin αIIbβ, in response to platelet activation, leads to the binding of fibrinogen, promoting the formation of a thrombus [2]. Such a process could induce a partial or complete occlusion of the blood vessel, which leads to a decrease or blockage of the blood flow and becomes a cause of occurrence of ischemia or infarction of an irrigated organ such as the heart [3]
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