Niemann-Pick C1 protein regulates platelet membrane-associated calcium ion signaling in thrombo-occlusive diseases in mice.
| Autor: | Manke MC; DFG Heisenberg Group Thrombocardiology; Department of Cardiology, Angiology and Cardiovascular Medicine, University of Tübingen, Germany., Roslan A; Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Germany., Walker B; DFG Heisenberg Group Thrombocardiology., Münzer P; DFG Heisenberg Group Thrombocardiology; Department of Cardiology, Angiology and Cardiovascular Medicine, University of Tübingen, Germany., Kollotzek F; DFG Heisenberg Group Thrombocardiology; Department of Cardiology, Angiology and Cardiovascular Medicine, University of Tübingen, Germany., Peng B; Leibniz-Institut für Analytische Wissenschaften-ISAS, Dortmund, Germany; Division of Rheumatology, Department of Medicine Solna, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden., Mencl S; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Coman C; Department of Analytical Chemistry, University of Vienna, Austria., Szepanowski RD; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Schulze H; Institute of Experimental Biomedicine, University Hospital Würzburg, Germany., Lieberman AP; Department of Pathology, University of Michigan Medical School, USA., Lang F; Department of Physiology, University of Tübingen, Germany., Gawaz M; DFG Heisenberg Group Thrombocardiology., Kleinschnitz C; Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Lukowski R; Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Germany., Ahrends R; Leibniz-Institut für Analytische Wissenschaften-ISAS, Dortmund, Germany; Department of Analytical Chemistry, University of Vienna, Austria., Bobe R; HITh, UMR_S1176, INSERM, Université Paris-Saclay, France., Borst O; DFG Heisenberg Group Thrombocardiology; Department of Cardiology, Angiology and Cardiovascular Medicine, University of Tübingen, Germany. Electronic address: oliver.borst@med.uni-tuebingen.de. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2023 Jul; Vol. 21 (7), pp. 1957-1966. Date of Electronic Publication: 2023 Apr 11. |
| DOI: | 10.1016/j.jtha.2023.03.038 |
| Abstrakt: | 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.) |
| Databáze: | MEDLINE |
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