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Adiponectin receptor agonist AdipoRon modulates human and mouse platelet function

Abstract

Adiponectin, an adipokine secreted by adipocytes, has anti-atherosclerotic and antithrombotic activities. AdipoRon is synthetic small molecule adiponectin receptor agonist. In this study, we investigated the effect of AdipoRon on platelet activation and thrombus formation. Washed human platelets were prepared from the peripheral blood of healthy donors. In a series of in vitro platelet functional assays, pre-treatment with AdipoRon (10, 20, 40 µg/mL) dose-dependently inhibited the aggregation, granule secretion and spreading of washed human platelets. We showed that AdipoRon (20, 40 µg/mL) significantly inhibited AMPK, Syk, PLCγ2, PI3K, Akt, p38-MAPK and ERK1/2 signalling pathways in washed human platelets. In addition, we demonstrated that the phosphorylation of CKII at Tyr255 was an important mechanism of the integrin αIIbβ3-mediated platelet activation. Meanwhile, AdipoR1 deficiency impaired the inhibitory effect of AdipoRon on mouse platelets. In ferric chloride-induced carotid injury model, injection of AdipoRon (5 or 12.5 mg/kg, iv) significantly attenuated arterial thrombosis. In conclusion, AdipoRon attenuates platelet function via the AdipoR1/AMPK/CKII/PI3K/AKT signalling pathways, while exerting a protective effect against arterial thrombosis. This study offers new insights into the fields of cardiovascular disease and antiplatelet drug discovery.

Schematic model of AdipoRon regulating platelet activation. (BioRender.com)

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Fig. 1: Effect of AdipoRon on platelet aggregation.
Fig. 2: AdipoRon inhibits platelet granule secretion, calcium mobilisation, and mitochondrial respiration.
Fig. 3: AdipoRon inhibits platelet integrin αIIbβ3 outside-in signalling in vitro.
Fig. 4: Effect of AdipoRon on arterial thrombosis and venous thrombosis in vivo.
Fig. 5: AdipoRon inhibited the related signalling molecules AMPK, ACC, Syk, PLCγ2, PI3K, AKT, p38-MAPK, and ERK1/2.
Fig. 6: AdipoRon is associated with CKII (Tyr255) phosphorylation in platelets.
Fig. 7: AdipoR1 deficiency impairs the effect of AdipoRon.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 31620103909 to YH and No. 81800134 to ZPC) and the Fundamental Research Funds for the Central Universities (HUST: 2021yjsCXCY122) to XHZ. We would like to thank Prof Jun-ling Liu’s team from the Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, for providing αIIbβ3-CHO cells for our experiment.

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YH designed the study. XHZ, ZPC conducted the experiments and analysed data. XHZ, ZPC and YH drafted the manuscript. ML, WYL, LLL and ZYM helped perform the experiments. All authors read and approved the manuscript.

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Correspondence to Yu Hu.

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Zhou, Xh., Cheng, Zp., Lu, M. et al. Adiponectin receptor agonist AdipoRon modulates human and mouse platelet function. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00943-1

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  • DOI: https://doi.org/10.1038/s41401-022-00943-1

Keywords

  • adiponectin
  • adipoRon
  • platelet activation
  • signalling pathway
  • thrombosis
  • antiplatelet drug

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