| First Author | Manke MC | Year | 2023 |
| Journal | J Thromb Haemost | Volume | 21 |
| Issue | 7 | Pages | 1957-1966 |
| PubMed ID | 37054918 | Mgi Jnum | J:355577 |
| Mgi Id | MGI:7715047 | Doi | 10.1016/j.jtha.2023.03.038 |
| Citation | Manke MC, et al. (2023) Niemann-Pick C1 protein regulates platelet membrane-associated calcium ion signaling in thrombo-occlusive diseases in mice. J Thromb Haemost 21(7):1957-1966 |
| abstractText | 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. |
