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Journal of Internal Medicine Jul 2024Platelet hyperreactivity and hyperlipidaemia contribute significantly to atherosclerosis. Thus, it is desirable to review the platelet-hyperlipidaemia interplay and its... (Review)
Review
Platelet hyperreactivity and hyperlipidaemia contribute significantly to atherosclerosis. Thus, it is desirable to review the platelet-hyperlipidaemia interplay and its impact on atherogenesis. Native low-density lipoprotein (nLDL) and oxidized LDL (oxLDL) are the key proatherosclerotic components of hyperlipidaemia. nLDL binds to the platelet-specific LDL receptor (LDLR) ApoE-R2', whereas oxLDL binds to the platelet-expressed scavenger receptor CD36, lectin-type oxidized LDLR 1 and scavenger receptor class A 1. Ligation of nLDL/oxLDL induces mild platelet activation and may prime platelets for other platelet agonists. Platelets, in turn, can modulate lipoprotein metabolisms. Platelets contribute to LDL oxidation by enhancing the production of reactive oxygen species and LDLR degradation via proprotein convertase subtilisin/kexin type 9 release. Platelet-released platelet factor 4 and transforming growth factor β modulate LDL uptake and foam cell formation. Thus, platelet dysfunction and hyperlipidaemia work in concert to aggravate atherogenesis. Hypolipidemic drugs modulate platelet function, whereas antiplatelet drugs influence lipid metabolism. The research prospects of the platelet-hyperlipidaemia interplay in atherosclerosis are also discussed.
Topics: Humans; Atherosclerosis; Hyperlipidemias; Blood Platelets; Lipoproteins, LDL; Platelet Activation; Receptors, LDL; Hypolipidemic Agents
PubMed: 38704820
DOI: 10.1111/joim.13794 -
Journal of Thrombosis and Haemostasis :... Jul 2023Pathophysiologic platelet activation leads to thrombo-occlusive diseases such as myocardial infarction or ischemic stroke. Niemann-Pick C1 protein (NPC1) is involved in...
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) signaling, and its genetic mutation causes a lysosomal storage disorder. Lipids and Ca are key players in the complex orchestration of platelet activation.
OBJECTIVES
The present study aimed to determine the impact of NPC1 on Ca mobilization during platelet activation in thrombo-occlusive diseases.
METHODS
Using MK/platelet-specific knockout mice of Npc1 (Npc1), 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 platelets display increased sphingosine levels and a locally impaired membrane-associated and SERCA3-dependent Ca mobilisation compared to platelets from wildtype littermates (Npc1). Further, we observed decreased platelet.
CONCLUSION
Our findings highlight that NPC1 regulates membrane-associated and SERCA3-dependent Ca 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.
Topics: Mice; Animals; Niemann-Pick C1 Protein; Calcium; Intracellular Signaling Peptides and Proteins; Niemann-Pick Disease, Type C; Mice, Knockout
PubMed: 37054918
DOI: 10.1016/j.jtha.2023.03.038 -
Gas plasma-induced platelet activation corresponds to reactive species profiles and lipid oxidation.Free Radical Biology & Medicine Oct 2023Surgical-induced hemostasis is a critical step in the closure of incisions, which is frequently achieved via electrocauterization and subsequent tissue necrotization....
Surgical-induced hemostasis is a critical step in the closure of incisions, which is frequently achieved via electrocauterization and subsequent tissue necrotization. The latter is associated with postoperative complications. Recent in vivo work suggested reactive species-producing gas plasma technology as a pro-homeostatic agent acting via platelet activation. However, it remained elusive how platelet activation is linked to lipid and protein oxidation and the reactive species compositions. A direct relation between the reactive species composition and platelet activation was revealed by assessing the production of several reactive species and by using antioxidants. In addition, platelet lipidome and proteome analysis identified significantly regulated key lipids in the platelet activation pathway, such as diacylglycerols and phosphatidylinositol as well as oxylipins like thromboxanes. Lipid oxidation products mainly derived from phosphatidylethanolamine and phosphatidylserine species were observed at modest levels. In addition, oxidative post-translational modifications were identified on key proteins of the hemostasis machinery. This study provides new insights into oxidation-induced platelet activation in general and suggests a potential role of those processes in gas plasma-mediated hemostasis in particular.
Topics: Platelet Activation; Blood Platelets; Oxidation-Reduction; Antioxidants; Lipids
PubMed: 37490986
DOI: 10.1016/j.freeradbiomed.2023.07.024 -
Seminars in Thrombosis and Hemostasis Sep 2023Heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT) are highly prothrombotic (thrombosis frequency ≥50%). Both are... (Review)
Review
Heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT) are highly prothrombotic (thrombosis frequency ≥50%). Both are caused by platelet-activating anti-platelet factor 4 (PF4) antibodies, forming PF4/IgG-containing immune complexes that engage platelet FcγIIa receptors, producing strong platelet activation. In HIT, heparin crosslinks several PF4 molecules, whereas in VITT, anti-PF4 antibodies alone crosslink PF4. Sufficient levels of circulating anti-PF4 antibodies are needed to create the pathogenic immune complexes on platelet surfaces; this explains why certain serum (plasma)-based assays are highly sensitive for detecting HIT/VITT antibodies. Accordingly, HIT and VITT are "clinical-pathological" disorders, that is, positive testing for such antibodies-together with a compatible clinical picture-is integral for diagnosis. Heparin (low concentrations) HIT antibody-induced platelet activation, but platelet activation by VITT sera is usually by heparin. For both HIT and VITT, high sensitivity (>99% and >95%, respectively) characterizes PF4-dependent enzyme immunoassays (EIAs) and PF4-enhanced platelet activation assays; in contrast, certain rapid immunoassays have high sensitivity for HIT (>90-97%) but poor sensitivity (<25%) for VITT. HIT and VITT antibodies are directed at distinct sites on PF4: solid-phase EIAs and platelet activation assays are indifferent to these distinct antigen targets, but rapid immunoassays are not. We discuss a conceptual model where PF4 is viewed as a "globe," with the heparin-binding site the "equator"; in this model, HIT antibodies are primarily directed at antigen site(s) at the north and south "poles" of PF4 (formed when PF4 binds to heparin), whereas VITT antibodies recognize sites on the equator.
Topics: Humans; Antigen-Antibody Complex; Thrombocytopenia; Heparin; Purpura, Thrombocytopenic, Idiopathic; Thrombosis
PubMed: 36455619
DOI: 10.1055/s-0042-1758818 -
International Journal of Molecular... Jul 2023Zinc (Zn) is released by platelets during a hemostatic response to injury. Extracellular zinc ([Zn]) initiates platelet activation following influx into the platelet...
Zinc (Zn) is released by platelets during a hemostatic response to injury. Extracellular zinc ([Zn]) initiates platelet activation following influx into the platelet cytosol. However, the mechanisms that permit Zn influx are unknown. Fluctuations in intracellular zinc ([Zn]) were measured in fluozin-3-loaded platelets using fluorometry and flow cytometry. Platelet activation was assessed using light transmission aggregometry. The detection of phosphoproteins was performed by Western blotting. [Zn] influx and subsequent platelet activation were abrogated by blocking the sodium/calcium exchanged, TRP channels, and ZIP7. Cation store depletion regulated Zn influx. [Zn] stimulation resulted in the phosphorylation of PKC substates, MLC, and β3 integrin. Platelet activation via GPVI or Zn resulted in ZIP7 phosphorylation in a casein kinase 2-dependent manner and initiated elevations of [Zn] that were sensitive to the inhibition of Orai1, ZIP7, or IPR-mediated pathways. These data indicate that platelets detect and respond to changes in [Zn] via influx into the cytosol through TRP channels and the NCX exchanger. Platelet activation results in the externalization of ZIP7, which further regulates Zn influx. Increases in [Zn] contribute to the activation of cation-dependent enzymes. Sensitivity of Zn influx to thapsigargin indicates a store-operated pathway that we term store-operated Zn entry (SOZE). These mechanisms may affect platelet behavior during thrombosis and hemostasis.
Topics: Cation Transport Proteins; Zinc; Endoplasmic Reticulum; Platelet Activation; Blood Platelets; Cations; Calcium
PubMed: 37511448
DOI: 10.3390/ijms241411689 -
Cells Jul 2023Platelets are cellular elements that are physiologically involved in hemostasis, inflammation, thrombotic events, and various human diseases. There is a link between the... (Review)
Review
Platelets are cellular elements that are physiologically involved in hemostasis, inflammation, thrombotic events, and various human diseases. There is a link between the activation of platelets and their metabolism. Platelets possess considerable metabolic versatility. Although the role of platelets in hemostasis and inflammation is known, our current understanding of platelet metabolism in terms of substrate preference is limited. Platelet activation triggers an oxidative metabolism increase to sustain energy requirements better than aerobic glycolysis alone. In addition, platelets possess extra-mitochondrial oxidative phosphorylation, which could be one of the sources of chemical energy required for platelet activation. This review aims to provide an overview of flexible platelet metabolism, focusing on the role of metabolic compartmentalization in substrate preference, since the metabolic flexibility of stimulated platelets could depend on subcellular localization and functional timing. Thus, developing a detailed understanding of the link between platelet activation and metabolic changes is crucial for improving human health.
Topics: Humans; Blood Platelets; Glycolysis; Platelet Activation; Energy Metabolism; Inflammation
PubMed: 37443836
DOI: 10.3390/cells12131802 -
Arteriosclerosis, Thrombosis, and... Aug 2023Blood flow-induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating... (Review)
Review
Blood flow-induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating cells, triggering the rapid activation of receptors, calcium channels, and related signaling mechanisms. Shear stress can also modify the folding of extracellular molecules and directly activate mechanosensitive receptors and calcium channels. The mechanical movement of the extracellular matrix and the intracellular cortical actin cytoskeleton can change the conformation of platelet receptors and gate channel pores in the plasma membrane. Mechanosensitive platelet receptors and their downstream signaling events and metabolic products can also indirectly activate calcium channels. While the molecular composite of mechanotransduction pathways has been described in mammals, shear stress-induced platelet receptors and their cross talk with calcium channels have been incompletely characterized. In this review, we discuss current knowledge about the role of mechanosensitive platelet receptors and calcium channels in shear-dependent platelet activation and arterial thrombus formation.
Topics: Animals; Blood Platelets; Calcium Channels; Mechanotransduction, Cellular; Platelet Activation; Signal Transduction; Calcium; Stress, Mechanical; Mammals
PubMed: 37345523
DOI: 10.1161/ATVBAHA.123.318341 -
Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk.Blood Apr 2024JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial... (Meta-Analysis)
Meta-Analysis
JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre-mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2VF CH, both Jak2VF and wild-type (WT) platelets showed increased activation, suggesting cross talk between mutant and WT platelets. Jak2VF platelets showed twofold to threefold upregulation of COX-1 and COX-2, particularly in young platelets, with elevated cPLA2 activation and thromboxane A2 production. Compared with controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin ameliorated carotid artery thrombosis in VFGp1ba and Jak2VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH with a major role of increased reticulated Jak2VF platelets, which mediate thromboxane cross talk with WT platelets and suggests a potential beneficial effect of aspirin in JAK2VF CH.
Topics: Animals; Humans; Mice; Aspirin; Blood Platelets; Clonal Hematopoiesis; Mice, Knockout; Platelet Activation; Thrombosis
PubMed: 38142422
DOI: 10.1182/blood.2023022260 -
Platelets Dec 2023Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these...
Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these complications, however platelet lipidomics have not been studied yet. The aim of our pilot investigation was to perform a preliminary study of platelet lipidomics in COVID-19 patients compared to healthy subjects. Lipid extraction and identification of ultrapurified platelets from eight hospitalized COVID-19 patients and eight age- and sex-matched healthy controls showed a lipidomic pattern almost completely separating COVID-19 patients from healthy controls. In particular, a significant decrease of ether phospholipids and increased levels of ganglioside GM3 were observed in platelets from COVID-19 patients. In conclusion, our study shows for the first time that platelets from COVID-19 patients display a different lipidomics signature distinguishing them from healthy controls, and suggests that altered platelet lipid metabolism may play a role in viral spreading and in the thrombotic complications of COVID-19.
Topics: Humans; COVID-19; Lipidomics; Blood Platelets; Platelet Activation; Thrombosis
PubMed: 37114418
DOI: 10.1080/09537104.2023.2200847 -
Life Sciences Aug 2023Platelet activation plays a central role in arterial thrombosis. Platelets are activated by adhesive proteins (i.e., collagen) or soluble agonists (i.e., thrombin), the...
AIMS
Platelet activation plays a central role in arterial thrombosis. Platelets are activated by adhesive proteins (i.e., collagen) or soluble agonists (i.e., thrombin), the respective receptor-specific signaling cause inside-out signaling, leading to the binding of fibrinogen to integrin αβ. This binding triggers outside-in signaling, resulting in platelet aggregation. Garcinol, a polyisoprenylated benzophenone, is extracted from the fruit rind of Garcinia indica. Although garcinol exhibits considerable bioactivities, few studies have investigated the effect of garcinol on platelet activation.
MAIN METHODS
Aggregometry, immunoblotting, flow cytometer, confocal microscopic analysis, fibrin clot retraction, animal studies such as fluorescein-induced platelet plug formation in mesenteric microvessels, acute pulmonary thromboembolism, and tail bleeding time were performed in this study.
KEY FINDINGS
This study indicates that garcinol inhibited platelet aggregation stimulated by collagen, thrombin, arachidonic acid, and U46619. Garcinol reduced integrin αβ inside-out signaling, including ATP release; cytosolic Ca mobilization; P-selectin expression; and Syk, PLCγ2/PKC, PI3K/Akt/GSK3β, MAPKs, and NF-κB activation stimulated by collagen. Garcinol directly inhibited integrin αβ activation by interfering with FITC-PAC-1 and FITC-triflavin by collagen. Additionally, garcinol affected integrin αβ-mediated outside-in signaling, such as decreasing platelet adhesion and the single-platelet spreading area; suppressing integrin β, Src, FAK, and Syk phosphorylation on immobilized fibrinogen; and inhibiting thrombin-stimulated fibrin clot retraction. Garcinol substantially reduced mortality caused by pulmonary thromboembolism and prolonged the occlusion time of thrombotic platelet plug formation without extending bleeding time in mice.
SIGNIFICANCE
This study identified that garcinol, a novel antithrombotic agent, acts as a naturally occurring integrin αβ inhibitor.
Topics: Humans; Mice; Animals; Blood Platelets; Platelet Glycoprotein GPIIb-IIIa Complex; Fluorescein-5-isothiocyanate; Phosphatidylinositol 3-Kinases; Thrombin; Platelet Activation; Platelet Aggregation; Thrombosis; Phosphorylation; Collagen; Fibrinogen; Pulmonary Embolism
PubMed: 37211346
DOI: 10.1016/j.lfs.2023.121791