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CME Evaluation

Oral Communication Session

Platelets and Megakaryocytes

Session: Platelet biology discovery

OC 28.4 - Hippo pathway effector TAZ negatively regulates platelet activation and thrombosis by inhibiting MEK-ERK-cPLA2 pathway

Sunday, June 23, 2024
15:30 – 15:45 ICT
Room: 211 A-D

    Presenting Author(s)

  • Xiaowen Wu, MA

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

    • Co-Author(s)

  • GP

    Guanxing Pan

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

  • YZ

    Yulong Zhang, MD

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

  • ZZ

    Zhiling Zhang

    none
    Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
    Shanghai, Shanghai, China (People's Republic)

  • YG

    Yifan Guo

    none
    Department of Cardiology, Tianjin Medical University General Hospital
    Tianjin, Tianjin, China (People's Republic)

  • LL

    Li Li

    none
    Intensive Care Unit, The Second Hospital of 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)

  • MD

    Meng Du

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

  • QL

    Qian Liu

    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)

  • ZZ

    Zhiqiang Zhao

    Professor
    Departement of Cardiology,The Second Hospital of Tianjin Medical University
    Tianjin, Tianjin, China (People's Republic)

  • FY

    Fa-xing Yu

    Professor
    Institutes of Biomedical Sciences, Fudan University
    Shanghai, Shanghai, China (People's Republic)

  • SX

    Shaopeng Xu

    Professor
    Department of Cardiology, Tianjin Medical University General Hospital
    Tianjin, Tianjin, China (People's Republic)

  • QY

    Qing Yang

    Professor
    Department of Cardiology, Tianjin Medical University General Hospital
    Tianjin, Tianjin, China (People's Republic)

  • BC

    Bing Chen

    Professor
    Intensive Care Unit,The Second Hospital of Tianjin Medical University
    Tianjin, Tianjin, China (People's Republic)

  • XC

    Xiongwen Chen

    Professor
    School of Pharmacy, Tianjin Medical University
    Tianjin, Tianjin, 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: Platelet abnormal activation and intravascular thrombosis causes serious adverse cardiovascular events. The expression and function of Hippo pathway effector TAZ is completely unknown in platelets.

Aims: To investigate the role and mechanism of TAZ in platelet activation and thrombosis.

Methods: Blood from healthy volunteers, patients with ACS (acute coronary syndrome), and mice was collected; RT-PCR, Western blot, and laser confocal microscopy were used to detect the expression and localization of TAZ in platelets. Platelet-specific TAZ knockout mice were established by crossing PF4-Cre mice with TAZ-floxed mice. The effects of TAZ on platelet aggregation, ATP release, spreading, and clot retraction were assayed using platelets from wild type and platelet-specific TAZ knockout mice. Thrombosis and hemostasis were detected using the FeCl3-induced mouse mesenteric arteriole thrombosis model and measuring mouse bleeding time and volume. Co-immunoprecipitation was used to detect TAZ-interacting proteins. Phosphorylation of signaling molecules downstream of TAZ during platelet activation was also measured.

Results: Human and mouse platelets express TAZ at both mRNA and protein levels, and TAZ are mainly distributed in platelet cytoplasm. Platelets from patients with ACS express significantly lower levels of TAZ at the protein level than the healthy donors. TAZ deficiency promotes mouse platelet aggregation and ATP release induced by multiple agonists; platelet spreading on fibrinogen and clot retraction are also enhanced. Thrombus formation in mesenteric arteriole and hemostasis are significantly enhanced in TAZ deficient mice. Mechanically, TAZ inhibits phosphorylation of c-Raf to activate downstream kinases by interacting with p-c-Raf in resting platelets. When platelets are activated, p-c-RAF-TAZ interaction is impaired, releasing the inhibition on MEK-ERK-cPLA2 pathway. In the absence of TAZ, the braking effect of TAZ on MEK-ERK-cPLA2 pathway is totally removed, leading to exaggerated platelet activation.

Conclusion(s): TAZ negatively regulates platelet activation and thrombosis via inhibiting MEK-ERK-cPLA2 pathway.