GDF-15 Inhibits ADP-Induced Human Platelet Aggregation through the GFRAL/RET Signaling Complex

  • Biomolecules. 2023 Dec 27;14(1):38. doi: 10.3390/biom14010038.
Baikang Xie  1  2  3 ,  Wenjing Tang  1  2  3 ,  Shuang Wen  4 ,  Fen Chen  1  2  3 ,  Chao Yang  5 ,  Min Wang  1  2  3 ,  Yong Yang  1  2  3 ,  Wei Liang  1  2  3
Affiliations
  • 1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2. Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 3. Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 4. Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 5. Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
PMID: 38254638 DOI: 10.3390/biom14010038
Abstract

Growth differentiation factor-15 (GDF-15) is proposed to be strongly associated with several cardiovascular diseases, such as heart failure and atherosclerosis. Moreover, some recent studies have reported an association between GDF-15 and platelet activation. In this study, we isolated peripheral blood platelets from healthy volunteers and evaluated the effect of GDF-15 on adenosine diphosphate (ADP)-induced platelet activation using the platelet aggregation assay. Subsequently, we detected the expression of GDF-15-related receptors on platelets, including the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), transforming growth factor-beta receptor I (TGF-βRI), transforming growth factor-beta receptor II (TGF-βRII), glial-cell-line-derived neurotrophic factor family receptor α-like (GFRAL), and those rearranged during transfection (RET). Then, we screened for GDF-15 receptors using the GDF-15-related receptor microarray comprising these recombinant proteins. We also performed the immunoprecipitation assay to investigate the interaction between GDF-15 and the receptors on platelets. For the further exploration of signaling pathways, we investigated the effects of GDF-15 on the extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and Janus kinase 2 (JAK2) pathways. We also investigated the effects of GDF-15 on the ERK and Akt pathways and platelet aggregation in the presence or absence of RET agonists or inhibition. Our study revealed that GDF-15 can dose-independently inhibit ADP-induced human platelet aggregation and that the binding partner of GDF-15 on platelets is GFRAL. We also found that GDF-15 inhibits ADP-induced Akt and ERK activation in platelets. Meanwhile, our results revealed that the inhibitory effects of GDF-15 can be mediated by the GFRAL/RET complex. These findings reveal the novel inhibitory mechanism of ADP-induced platelet activation by GDF-15.

Keywords
extracellular signal-regulated kinase; glial-cell-line-derived neurotrophic factor family receptor α-like; growth differentiation factor-15; platelet; protein kinase B.
Products
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  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110193
    SPP-86
    99.87%, RET Inhibitor
    target: RET
    Research Areas: Cancer
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