Suppressive effect of exogenous carbon monoxide on endotoxin-stimulated platelet over-activation via the glycoprotein-mediated PI3K-Akt-GSK3β pathway

Dadong Liu,Yawei Wang,Xu Wang,Bingwei Sun,Mingfeng Zhuang,Jingjia Chen,Weiting Qin

doi:10.1038/srep23653

Dadong Liu, Yawei Wang + Show 5 more

Open Access

https://doi.org/10.1038/srep23653

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Abstract

Platelet activation is an important event involved in the pathophysiological processes of the coagulation system. Clinical evidence has shown that platelets undergo distinctive pathological processes during sepsis. Unfortunately, how platelets physiologically respond to inflammation or sepsis is not well understood. In this study, we used a lipopolysaccharide (LPS)-stimulated platelet model to systemically investigate alterations in membrane glycoprotein expression, molecular signaling, morphology and critical functions of platelets. We found that platelet adhesion, aggregation, secretion, and spreading on immobilized fibrinogen and the expression of platelet membrane glycoproteins were significantly increased by LPS stimulation, and these changes were accompanied by a significant decrease in cGMP levels and an abnormal distribution of platelet α-granules. Exogenous CO reversed these alterations. Profound morphological changes in LPS-stimulated platelets were observed using atomic force microscopy and phase microscopy. Furthermore, the elevated activities of PI3Ks, AKt and GSK-3β were effectively suppressed by exogenous CO, leading to the improvement of platelet function. Together, these results provide evidence that platelet over-activation persists under LPS-stimulation and that exogenous CO plays an important role in suppressing platelet activation via the glycoprotein-mediated PI3K-Akt-GSK3β pathway.

Highlights

To facilitate the pharmaceutical use of CO by delivering it to the affected tissues and organs[13,19]
On the basis of the above information, the present study was designed as a prospective experiment to investigate the effects of exogenous CO on the suppression of LPS-stimulated platelet activation and to explore whether the molecular mechanisms of this therapeutic effect of CO occur via the glycoprotein-mediated PI3K-Akt-GSK3β pathway
We found that LPS stimulation resulted in a significant increase in the levels of PI3Kβ and that this increase was abolished in LPS-stimulated platelets treated with CO-releasing molecules (CORMs)-2 (Fig. 5E and Supplementary Figure 5B)

Summary

Introduction

To facilitate the pharmaceutical use of CO by delivering it to the affected tissues and organs[13,19]. The results show that the expression of membrane glycoproteins was significantly upregulated in LPS-stimulated platelets, whereas exogenous CO administration inhibited this upregulation (Fig. 4D–F). Administration of exogenous CO may effectively elevate cGMP levels in LPS-stimulated platelets, resulting in a suppression of platelet activation.

Results

Conclusion