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Poster Networking

Platelets and Megakaryocytes

PB0775 - Platelet TNIK promotes hemostasis while prevents hyperlipidemia-associated thrombosis

Monday, June 24, 2024
13:45 – 14:45 ICT
Room: Exhibition Hall

    Presenting Author(s)

  • Fan Bu

    Medical doctor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

    • Co-Author(s)

  • LL

    Li Li

    medical doctor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

  • JL

    Jingke Li

    medical doctor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

  • XC

    Xiaoyan Chen

    medical doctor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

  • XD

    Xin Deng

    medical doctor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

  • YS

    Yilin Sheng

    medical doctor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

  • Hu Hu, PhD

    professor
    Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
    hangzhou, Zhejiang, China (People's Republic)

Background: A balanced platelet activation is essential for maintaining hemostasis and preventing pathological thrombosis, the latter being the major cause of morbidity and mortality associated with metabolic disorders such as hyperlipidemia. Both hemostatic and thrombotic responses of platelets are fine-tuned through a plethera of signal pathways centered on Mitogen-activated protein kinases (MAPKs). However, detailed mechanisms of how platelets may differentiate the signals required for hemostasis and thrombosis, respectively, is currently unknown. Traf2- and Nck-interacting kinase (TNIK) is a member of the germinal center kinase (GCK) IV family that acts as a MAP4K and is important in metabolic regulation of lipids, yet the role of platelet TNIK in regulating hemostasis and thrombosis, especially under hyperlipidemia remains undetermined.

Aims: To investigate the role of platelet TNIK in hemostasis and hyperlipidemia-associated thrombosis.

Methods: Hemostasis and thrombosis was evaluated in a megakaryocyte-platelet-specific TNIK-knockout mouse (TNIKf/f PF4-Cre+) strain and high fat diet (HFD)-fed ApoE-/- mice transplanted with bone marrow from TNIKf/f PF4-Cre+ mice (TNIKf/f PF4-Cre+ ApoE-/-). Biochemistry and platelet functional assays were employed to evaluate the signaling mechanism of TNIK in platelets.

Results: TNIKf/f PF4-Cre+ mice displayed a prolonged mesenteric arteriolar occlusion and tail-bleeding time, whereas hyperlipidemic mice in the absence of platelet TNIK (HFD TNIKf/f PF4-Cre+ ApoE-/-) exhibited a drastically enhanced thrombotic response. TNIK-/- platelets showed an impaired aggregation in response to thrombin and collagen, due mainly to a dampened dense granule secretion. Surprisingly, TNIK-/- platelets responded to oxidized low-density lipoprotein (OxLDL) with an enhanced aggregation. Mechanistically, under thrombin or collagen stimulation, platelet TNIK binds to JNK-interacting protein 1 (JIP-1) and activates JNK pathways, while in oxLDL-stimulated platelets, TNIK specifically binds to protein kinase C epsilon (PKCĪµ), which leads to an inhibition of NOX2/ROS/ERK5 pathway.

Conclusion(s): Platelet TNIK promotes hemostasis while prevents hyperlipidemia-associated thrombosis.