Journal of thrombosis and haemostasis : JTH · 2025
Mitogen-activated protein kinase 1 regulates platelet function and thrombus formation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Xu Xiaoqi, Dai Yue, Zhu Hui, Zhang Jie, Li Yingying, Jiang Huimin, Chu Xiang, Sun Yueyue, Ju Wen, Xu Mengdi, Zeng Lingyu, Li Zhenyu, Xu Kailin, Qiao Jianlin
Аннотация
BACKGROUND: Mitogen-activated protein kinase (MAPK)1 or ERK2 is a Ser/Thr kinase, and its inhibition by pharmacologic inhibitors attenuated platelet function. However, conflicting results for different inhibitors were obtained due to off-target effects. Moreover, whether MAPK1 affects platelet function is unknown.
OBJECTIVES: This study intended to evaluate the role of MAPK1 in platelet activity and thrombus formation.
METHODS: Megakaryocyte/platelet-specific MAPK1 knockout mice were generated and used to assess platelet aggregation, activation, procoagulant activity, spreading and clot retraction. In addition, tail bleeding time and arterial and venous thrombus formation assays were performed to evaluate the in vivo hemostatic function and thrombus formation.
RESULTS: MAPK1 deficiency impaired hemostasis, both arterial and venous thrombosis. Consistently, MAPK1-deficient platelets presented reduced platelet aggregation, granule release, αIIbβ3 activation, calcium mobilization, procoagulant activity, and spreading and clot retraction. Additionally, MAPK1 deficiency inhibited phosphorylation of p38, ERK5, JNK, and ASK1 as well as the release of arachidonic acid and thromboxane B2. Moreover, MAPK1 interacts with talin1 and phosphorylates it at Ser425 in activated platelets, and its deletion impaired the phosphorylation of talin1 and β3. Furthermore, inhibition of platelet feedback signaling by apyrase abolished the difference of platelet aggregation compared with control platelets and inhibited the phosphorylation of ASK1 and talin1 in activated control platelets. Finally, inhibition of MAPK1 decreased human platelet function and reduced the phosphorylation of talin1 and β3.
CONCLUSION: Our study identifies a novel mechanism for MAPK1 in the regulation of platelet function and thrombosis, implying its potential as a target to treat thrombotic disorders.
OBJECTIVES: This study intended to evaluate the role of MAPK1 in platelet activity and thrombus formation.
METHODS: Megakaryocyte/platelet-specific MAPK1 knockout mice were generated and used to assess platelet aggregation, activation, procoagulant activity, spreading and clot retraction. In addition, tail bleeding time and arterial and venous thrombus formation assays were performed to evaluate the in vivo hemostatic function and thrombus formation.
RESULTS: MAPK1 deficiency impaired hemostasis, both arterial and venous thrombosis. Consistently, MAPK1-deficient platelets presented reduced platelet aggregation, granule release, αIIbβ3 activation, calcium mobilization, procoagulant activity, and spreading and clot retraction. Additionally, MAPK1 deficiency inhibited phosphorylation of p38, ERK5, JNK, and ASK1 as well as the release of arachidonic acid and thromboxane B2. Moreover, MAPK1 interacts with talin1 and phosphorylates it at Ser425 in activated platelets, and its deletion impaired the phosphorylation of talin1 and β3. Furthermore, inhibition of platelet feedback signaling by apyrase abolished the difference of platelet aggregation compared with control platelets and inhibited the phosphorylation of ASK1 and talin1 in activated control platelets. Finally, inhibition of MAPK1 decreased human platelet function and reduced the phosphorylation of talin1 and β3.
CONCLUSION: Our study identifies a novel mechanism for MAPK1 in the regulation of platelet function and thrombosis, implying its potential as a target to treat thrombotic disorders.