Abstract
Phospholipase D (PLD) is involved in many biological processes. PLD1 plays a crucial role in regulating the platelet activity of mice; however, the role of PLD in the platelet activation of humans remains unclear. Therefore, we investigated whether PLD is involved in the platelet activation of humans. Our data revealed that inhibition of PLD1 or PLD2 using pharmacological inhibitors effectively inhibits platelet aggregation in humans. However, previous studies have showed that PLD1 or PLD2 deletion did not affect mouse platelet aggregation in vitro, whereas only PLD1 deletion inhibited thrombus formation in vivo. Intriguingly, our data also showed that the pharmacological inhibition of PLD1 or PLD2 does not affect mouse platelet aggregation in vitro, whereas the inhibition of only PLD1 delayed thrombus formation in vivo. These findings indicate that PLD may play differential roles in humans and mice. In humans, PLD inhibition attenuates platelet activation, adhesion, spreading, and clot retraction. For the first time, we demonstrated that PLD1 and PLD2 are essential for platelet activation in humans, and PLD plays different roles in platelet function in humans and mice. Our findings also indicate that targeting PLD may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders.
Highlights
Platelets play a crucial role in normal haemostasis
The selective PLD1 inhibitor VU1 and PLD2 inhibitor VU2 have been used to evaluate the roles of PLD1 and PLD2, respectively, in a variety of cells [7,8,14]
Phospholipase D (PLD) may have different functions in humans and mice, but it in humans. is certain that both PLD1 and PLD2 are essential for platelet activation in humans
Summary
Platelets play a crucial role in normal haemostasis. When blood vessels are damaged, platelets are activated and form a platelet plug at the injury site to prevent blood loss. In 2014, the US Food and Drug Administration approved the thrombin receptor (protease-activated receptor 1) antagonist vorapaxar, a new category of antiplatelet drugs, for preventing secondary stroke. These novel antiplatelet drugs offer alternative therapeutic strategies for reducing recurrent stroke, depending on their mechanisms of antiplatelet activity. Platelets from Pld1−/− mice reportedly exhibit impaired integrin αIIbβ activation and shear stress-induced thrombus formation but do not exhibit impaired granule release or platelet aggregation [4]. Genetic deletion or pharmacological inhibition of both PLD1 and PLD2 synergistically blocked integrin αIIbβ activation and α-granule release but did not affect platelet aggregation [5,6]. In this study, the function and mechanism of PLD underlying human platelet activation were determined for the first time
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