Zhongguo shi yan xue ye xue za zhi · 2026
[Study on the Effects and Underlying Mechanisms of SGK3 in Regulating Platelet Function].
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Huang Qiu-Xia, Zhou Xuan-Ding, Li Qing, Dai Ke-Sheng, Yan Rong
Аннотация
OBJECTIVE: To investigate the effects of SGK3 on platelet function and the underlying molecular mechanisms using SGK3-specific degrader SGK3-PROTAC1.
METHODS: Western blot was used to detect SGK3 expression in human and mouse platelets, and to verify the degradation effect of SGK3-PROTAC1 on SGK3 protein. Platelets were pretreated with different concentrations of SGK3-PROTAC1, and platelet aggregation induced by the thromboxane A2 analog U46619 and thrombin was measured using a platelet aggregometer. Flow cytometry was used to evaluate the integrin αⅡbβ3 activation, P-selectin expression, and phosphatidylserine (PS) exposure in platelets. Platelet spreading assay and clot retraction assay were conducted to evaluate the effects of SGK3-PROTAC1 on adhesion, spreading, and coagulation-related functions. A FeCl3-induced mesenteric arterial thrombosis model was established, and tail bleeding time was measured to evaluate the effect of SGK3-PROTAC1 on arterial thrombosis. Finally, Western blot was used to detect the phosphorylation level of PKC substrate pleckstrin, so as to explore the downstream signaling pathway by which SGK3 regulates platelet function.
RESULTS: SGK3 was expressed in both human and mouse platelets. Treatment with SGK3-PROTAC1 markedly reduced SGK3 protein levels (P < 0.05). SGK3-PROTAC1 dose-dependently inhibited U46619-induced platelet aggregation, αⅡbβ3 activation, P-selectin expression, and PS exposure, but had no significant effect on the aforementioned indices induced by thrombin. Moreover, SGK3-PROTAC1 treatment did not alter platelet spreading on fibrinogen-coated surfaces or clot retraction efficiency. in vivo, experiments demonstrated that SGK3-PROTAC1 significantly delayed FeCl3-induced mesenteric arterial thrombosis formation and markedly prolonged tail bleeding time in mice, while exerting no obvious effect on peripheral platelet counts. Mechanistic investigations revealed that SGK3-PROTAC1 inhibited U46619-induced phosphorylation of PKC substrate pleckstrin in platelets, but had no significant impact on thrombin-mediated enhancement of PKC activity.
CONCLUSION: SGK3 participates in partial platelet activation processes by regulating the PKC signaling pathway, and may serve as a potential therapeutic target for platelet-related disorders.
METHODS: Western blot was used to detect SGK3 expression in human and mouse platelets, and to verify the degradation effect of SGK3-PROTAC1 on SGK3 protein. Platelets were pretreated with different concentrations of SGK3-PROTAC1, and platelet aggregation induced by the thromboxane A2 analog U46619 and thrombin was measured using a platelet aggregometer. Flow cytometry was used to evaluate the integrin αⅡbβ3 activation, P-selectin expression, and phosphatidylserine (PS) exposure in platelets. Platelet spreading assay and clot retraction assay were conducted to evaluate the effects of SGK3-PROTAC1 on adhesion, spreading, and coagulation-related functions. A FeCl3-induced mesenteric arterial thrombosis model was established, and tail bleeding time was measured to evaluate the effect of SGK3-PROTAC1 on arterial thrombosis. Finally, Western blot was used to detect the phosphorylation level of PKC substrate pleckstrin, so as to explore the downstream signaling pathway by which SGK3 regulates platelet function.
RESULTS: SGK3 was expressed in both human and mouse platelets. Treatment with SGK3-PROTAC1 markedly reduced SGK3 protein levels (P < 0.05). SGK3-PROTAC1 dose-dependently inhibited U46619-induced platelet aggregation, αⅡbβ3 activation, P-selectin expression, and PS exposure, but had no significant effect on the aforementioned indices induced by thrombin. Moreover, SGK3-PROTAC1 treatment did not alter platelet spreading on fibrinogen-coated surfaces or clot retraction efficiency. in vivo, experiments demonstrated that SGK3-PROTAC1 significantly delayed FeCl3-induced mesenteric arterial thrombosis formation and markedly prolonged tail bleeding time in mice, while exerting no obvious effect on peripheral platelet counts. Mechanistic investigations revealed that SGK3-PROTAC1 inhibited U46619-induced phosphorylation of PKC substrate pleckstrin in platelets, but had no significant impact on thrombin-mediated enhancement of PKC activity.
CONCLUSION: SGK3 participates in partial platelet activation processes by regulating the PKC signaling pathway, and may serve as a potential therapeutic target for platelet-related disorders.