PB0822 - The antiplatelet and antithrombotic effects of UDCA as a TREM2 agonist

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

YZ

Yulong Zhang, MD

none
School of Pharmacy, Tianjin Medical University, Tianjin, China
Tianjin, Tianjin, China (People's Republic)

Presenting Author(s)

Xiaowen Wu, MA

none
School of Pharmacy, Tianjin Medical University, Tianjin, China
Tianjin, Tianjin, China (People's Republic)

Co-Author(s)

QL

Qian Liu

none
School of Pharmacy, Tianjin Medical University
Tianjin, Tianjin, China (People's Republic)
MD

Meng Du

none
School of Pharmacy, Tianjin Medical University
Tianjin, Tianjin, China (People's Republic)
YW

Yixian Wang

none
School of Pharmacy, Tianjin Medical University
Tianjin, Tianjin, China (People's Republic)
MJ

Meina Jin

Lecturer
School of Pharmacy, Tianjin Medical University
Tianjin, Tianjin, China (People's Republic)
QY

Qingyuan Yang

none
School of Pharmacy, Tianjin Medical University
Tianjin, Tianjin, China (People's Republic)
GP

Guanxing Pan

none
Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University
fuzhou, Fujian, China (People's Republic)
ZD

Zhongren Ding

Professor
School of Pharmacy, Tianjin Medical University; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences , Fudan University; Department of Geriatrics, The Second Hospital of Tianjin Medical University
Tianjin, Tianjin, China (People's Republic)

Background: We recently found that TREM2 (triggering receptor expressed in myeloid cells 2) expressed on platelets negatively regulates platelet activation, playing an important role in arterial thrombotic diseases. A TREM2-activating antibody has been under clinical trial for Alzheimer’s disease, suggesting that targeting TREM2 may also be used as antiplatelet therapy. In this study, we explored the antiplatelet effects of UDCA (ursodeoxycholic acid) as a TREM2 receptor agonist.

Aims: To explore the antiplatelet effect of UDCA and its mechanism.

Methods: The effects of UDCA on platelet aggregation and ATP release induced by multiple agonists were assayed using a Lumi-Aggregometer. Effects of UDCA on clot spreading on immobilized fibrinogen and clot retraction were also measured. Intravital microcopy was used to investigate its antithrombotic effects on a FeCl3-injuried mouse mesenteric arteriole thrombosis model. Bleeding risk was evaluated by measuring bleeding time and blood loss after mouse tail tip snip. To delineate the antiplatelet mechanism of UDCA, we carried out molecular docking, surface plasmon resonance (SPR) assay, compared the antiplatelet effects of UDCA using platelets from wild type and TREM2-/- mice; we also checked the effects of UDCA on the phosphorylation of SHIP1 and Akt, the downstream signals of TREM2 receptor in platelets.

Results: UDCA inhibits both human and mouse platelet activation induced by multiple agonists. Platelet spreading on fibrinogen and clot retraction are also inhibited. UDCA inhibits mouse mesenteric arteriole thrombosis similarly to clopidogrel with less bleeding. Molecular docking and SPR assay suggest that UDCA is a TREM2 ligand. TREM2 deficiency impairs the antiplatelet effects of UDCA, indicating it inhibits platelet activation as a TREM2 receptor agonist. Consistently, UDCA enhances p-SHIP1 and impairs p-Akt in both human and mouse platelets.

Conclusion(s): UDCA is a TREM2 receptor agonist, may be repurposed as an effective and safe antiplatelet agent.