Background: Pathophysiologic platelet activation leads to thrombo-occlusive diseases such as myocardial infarction or ischemic stroke. Niemann-Pick C1 protein (NPC1) is involved in the regulation of lysosomal lipid trafficking and calcium ion (Ca 2+ ) signaling, and its genetic mutation causes a lysosomal storage disorder. Lipids and Ca 2+ are key players in the complex orchestration of platelet activation.
Objectives: The present study aimed to determine the impact of NPC1 on Ca 2+ mobilization during platelet activation in thrombo-occlusive diseases.
Methods: Using MK/platelet-specific knockout mice of Npc1 (Npc1 Pf4∆/Pf4∆ ), ex vivo and in vitro approaches as well as in vivo models of thrombosis, we investigated the effect of Npc1 on platelet function and thrombus formation.
Results: We showed that Npc1 Pf4∆/Pf4∆ platelets display increased sphingosine levels and a locally impaired membrane-associated and SERCA3-dependent Ca 2+ mobilisation compared to platelets from wildtype littermates (Npc1 lox/lox ). Further, we observed decreased platelet.
Conclusion: Our findings highlight that NPC1 regulates membrane-associated and SERCA3-dependent Ca 2+ mobilization during platelet activation and that MK/platelet-specific ablation of Npc1 protects against experimental models of arterial thrombosis and myocardial or cerebral ischemia/reperfusion injury.
Competing Interests: Declaration of competing interests There are no competing interests to disclose.
(Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)