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Goubran H, Ahmed S, Ragab G, Seghatchian J, Burnouf T. Platelet proteomics: Clinical implications - Decoding the black box! Transfus Apher Sci 2025; 64:104060. [PMID: 39719751 DOI: 10.1016/j.transci.2024.104060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2024]
Abstract
Platelets are anucleate blood cells traditionally associated with hemostasis but now increasingly recognized for their multifaceted roles in immunity, inflammation, and tissue repair. Advances in platelet proteomics, employing high-throughput techniques such as mass spectrometry, have significantly enhanced our understanding of platelet biology and its clinical implications in transfusion medicine. Platelet proteomics offers a retrospective view of physiological and pathological changes over the platelet's 7-10-day lifespan, making it a unique tool for studying cumulative biological events. Recent applications include the identification of biomarkers for cardiovascular, infectious, autoimmune diseases and cancer. In neurodegeneration and aging, platelets have been explored for their shared molecular pathways with neurons, with findings implicating Tau, amyloid-beta, and alpha-synuclein as potential biomarkers. Proteomics is also emerging as an important factor in the development of evidence-based, tailor-made platelet-derived therapies. While promising, platelet proteomics requires further standardization and computational advances to support transitioning from research to routine clinical practice.
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Affiliation(s)
- Hadi Goubran
- Saskatoon Cancer Centre, Saskatoon, SK, Canada; Department of Oncology, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
| | - Shahid Ahmed
- Saskatoon Cancer Centre, Saskatoon, SK, Canada; Department of Oncology, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
| | - Gaafar Ragab
- Rheumatology and Immunology Unit, Internal Medicine Department, Cairo University, Egypt
| | - Jerard Seghatchian
- International Consultancy in Modern Personalized Blood Components Therapies and Innovative DDR Strategies, London, England, UK
| | - Thierry Burnouf
- Graduate Institute of Biological Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
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2
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Severin S, Gratacap MP, Bouvet L, Borret M, Kpotor AO, Chicanne G, Xuereb JM, Viaud J, Payrastre B. Phosphoinositides take a central stage in regulating blood platelet production and function. Adv Biol Regul 2024; 91:100992. [PMID: 37793962 DOI: 10.1016/j.jbior.2023.100992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023]
Abstract
Blood platelets are produced by megakaryocytes through a complex program of differentiation and play a critical role in hemostasis and thrombosis. These anucleate cells are the target of antithrombotic drugs that prevent them from clumping in cardiovascular disease conditions. Platelets also significantly contribute to various aspects of physiopathology, including interorgan communications, healing, inflammation, and thromboinflammation. Their production and activation are strictly regulated by highly elaborated mechanisms. Among them, those involving inositol lipids have drawn the attention of researchers. Phosphoinositides represent the seven combinatorially phosphorylated forms of the inositol head group of inositol lipids. They play a crucial role in regulating intracellular mechanisms, such as signal transduction, actin cytoskeleton rearrangements, and membrane trafficking, either by generating second messengers or by directly binding to specific domains of effector proteins. In this review, we will explore how phosphoinositides are implicated in controlling platelet production by megakaryocytes and in platelet activation processes. We will also discuss the diversity of phosphoinositides in platelets, their role in granule biogenesis and maintenance, as well as in integrin signaling. Finally, we will address the discovery of a novel pool of phosphatidylinositol 3-monophosphate in the outerleaflet of the plasma membrane of human and mouse platelets.
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Affiliation(s)
- Sonia Severin
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Marie-Pierre Gratacap
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Laura Bouvet
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Maxime Borret
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Afi Oportune Kpotor
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Gaëtan Chicanne
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Jean-Marie Xuereb
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Julien Viaud
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Bernard Payrastre
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France; Laboratoire d'Hématologie, Centre de Référence des Pathologies Plaquettaires, Centre Hospitalier Universitaire de Toulouse Rangueil, F-31432, Toulouse, France.
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3
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Manole CG, Soare C, Ceafalan LC, Voiculescu VM. Platelet-Rich Plasma in Dermatology: New Insights on the Cellular Mechanism of Skin Repair and Regeneration. Life (Basel) 2023; 14:40. [PMID: 38255655 PMCID: PMC10817627 DOI: 10.3390/life14010040] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/30/2023] [Accepted: 12/19/2023] [Indexed: 01/24/2024] Open
Abstract
The skin's recognised functions may undergo physiological alterations due to ageing, manifesting as varying degrees of facial wrinkles, diminished tautness, density, and volume. Additionally, these functions can be disrupted (patho)physiologically through various physical and chemical injuries, including surgical trauma, accidents, or chronic conditions like ulcers associated with diabetes mellitus, venous insufficiency, or obesity. Advancements in therapeutic interventions that boost the skin's innate regenerative abilities could significantly enhance patient care protocols. The application of Platelet-Rich Plasma (PRP) is widely recognized for its aesthetic and functional benefits to the skin. Yet, the endorsement of PRP's advantages often borders on the dogmatic, with its efficacy commonly ascribed solely to the activation of fibroblasts by the factors contained within platelet granules. PRP therapy is a cornerstone of regenerative medicine which involves the autologous delivery of conditioned plasma enriched by platelets. This is achieved by centrifugation, removing erythrocytes while retaining platelets and their granules. Despite its widespread use, the precise sequences of cellular activation, the specific cellular players, and the molecular machinery that drive PRP-facilitated healing are still enigmatic. There is still a paucity of definitive and robust studies elucidating these mechanisms. In recent years, telocytes (TCs)-a unique dermal cell population-have shown promising potential for tissue regeneration in various organs, including the dermis. TCs' participation in neo-angiogenesis, akin to that attributed to PRP, and their role in tissue remodelling and repair processes within the interstitia of several organs (including the dermis), offer intriguing insights. Their potential to contribute to, or possibly orchestrate, the skin regeneration process following PRP treatment has elicited considerable interest. Therefore, pursuing a comprehensive understanding of the cellular and molecular mechanisms at work, particularly those involving TCs, their temporal involvement in structural recovery following injury, and the interconnected biological events in skin wound healing and regeneration represents a compelling field of study.
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Affiliation(s)
- Catalin G. Manole
- Department of Cellular and Molecular Biology and Histology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Ultrastructural Pathology Laboratory, “Victor Babeș” National Institute of Pathology, 050096 Bucharest, Romania
| | - Cristina Soare
- Department of Oncological Dermatology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laura Cristina Ceafalan
- Department of Cellular and Molecular Biology and Histology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Cell Biology, Neurosciences and Experimental Myology Laboratory, “Victor Babeș” National Institute of Pathology, 050096 Bucharest, Romania
| | - Vlad M. Voiculescu
- Department of Oncological Dermatology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Yang M, Jiang H, Ding C, Zhang L, Ding N, Li G, Zhang F, Wang J, Deng L, Liu J, Xu Y. STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion. Immunity 2023; 56:1013-1026.e6. [PMID: 36944334 DOI: 10.1016/j.immuni.2023.02.015] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 11/09/2022] [Accepted: 02/22/2023] [Indexed: 03/23/2023]
Abstract
Sepsis is a dysregulated inflammatory consequence of systemic infection. As a result, excessive platelet activation leads to thrombosis and coagulopathy, but we currently lack sufficient understanding of these processes. Here, using the cecal ligation and puncture (CLP) model of sepsis, we observed septic thrombosis and neutrophil extracellular trap formation (NETosis) within the mouse vasculature by intravital microscopy. STING activation in platelets was a critical driver of sepsis-induced pathology. Platelet-specific STING deficiency suppressed platelet activation and granule secretion, which alleviated sepsis-induced intravascular thrombosis and NETosis in mice. Mechanistically, sepsis-derived cGAMP promoted the binding of STING to STXBP2, the assembly of SNARE complex, granule secretion, and subsequent septic thrombosis, which probably depended on the palmitoylation of STING. We generated a peptide, C-ST5, to block STING binding to STXBP2. Septic mice treated with C-ST5 showed reduced thrombosis. Overall, platelet activation via STING reveals a potential strategy for limiting life-threatening sepsis-mediated coagulopathy.
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Affiliation(s)
- Mina Yang
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Haojie Jiang
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Chen Ding
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lin Zhang
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Nan Ding
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Guoming Li
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Fei Zhang
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jing Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Liufu Deng
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Junling Liu
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Yanyan Xu
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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5
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Paul M, Golla K, Kim H. Gelsolin Modulates Platelet Dense Granule Secretion and Hemostasis via the Actin Cytoskeleton. Thromb Haemost 2023; 123:219-230. [PMID: 36522181 DOI: 10.1055/s-0042-1758800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND OBJECTIVE The mechanisms underlying platelet granule release are not fully understood. The actin cytoskeleton serves as the platelet's structural framework that is remodeled upon platelet activation. Gelsolin is a calcium-dependent protein that severs and caps existing actin filaments although its role in modulating platelet granule exocytosis is unknown. METHODS The hemostatic function of wild-type (WT) and gelsolin null (Gsn-/- ) mice was measured ex vivo by rotational thromboelastometry analysis of whole blood. Platelets were purified from WT and Gsn-/- mouse blood and activated with thrombin. Platelet aggregation was assessed by light-transmission aggregometry. Clot retraction was measured to assess outside-in integrin signaling. Adenosine triphosphate (ATP) release and surface P-selectin were measured as markers of dense- and α-granule secretion, respectively. RESULTS The kinetics of agonist-induced aggregation, clot retraction, and ATP release were accelerated in Gsn-/- platelets relative to WT. However, levels of surface P-selectin were diminished in Gsn-/- platelets. ATP release was also accelerated in WT platelets pretreated with the actin-depolymerizing drug cytochalasin D, thus mimicking the kinetics observed in Gsn-/- platelets. Conversely, ATP release kinetics were normalized in Gsn-/- platelets treated with the actin polymerization agonist jasplakinolide. Rab27b and Munc13-4 are vesicle-priming proteins known to promote dense granule secretion. Co-immunoprecipitation indicates that the association between Rab27b and Munc13-4 is enhanced in Gsn-/- platelets. CONCLUSIONS Gelsolin regulates the kinetics of hemostasis by modulating the platelet's actin cytoskeleton and the protein machinery of dense granule exocytosis.
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Affiliation(s)
- Manoj Paul
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kalyan Golla
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hugh Kim
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
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6
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Hu JL, Zhang WJ. The role and pharmacological properties of P2Y12 receptor in cancer and cancer pain. Biomed Pharmacother 2023; 157:113927. [PMID: 36462316 DOI: 10.1016/j.biopha.2022.113927] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/22/2022] [Accepted: 10/24/2022] [Indexed: 12/05/2022] Open
Abstract
The G protein-coupled P2Y12 receptor (P2Y12R) was cloned in platelets and found to play a key role in maintaining platelet function in hemostasis and thrombosis, and these effects could be mediated by the P2Y12R. However, it has recently been found that P2Y12R-mediated the progression of tumor through interactions between platelets and tumor and stromal cells, as well as through products secreted by platelets. During tumor progression, tumor cells or other cells in the tumor microenvironment (such as immune cells) can secrete large amounts of ATP into the extracellular matrix, and extracellular ATP can be hydrolyzed into ADP. ADP is a P2Y12R activator and plays an important regulatory role in the proliferation and metastasis of tumor cells. P2Y12R is involved in platelet-cancer cell crosstalk and become a potential target for anticancer therapy. Moreover, tumor progression can induce pain, which seriously affects the quality of life of patients. P2Y12R is expressed in microglia and mediates the activities of microglial and participates in the occurrence of cancer pain. Conversely, inhibiting P2Y12R activation and down-regulating its expression has the effect of inhibiting tumor progression and pain. Therefore, P2Y12R can be a common therapeutic target for both. In this article, we explored the potential link between P2Y12R and cancer, discussed the intrinsic link of P2Y12R in cancer pain and the pharmacological properties of P2Y12R antagonists in the treatment of both.
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Affiliation(s)
- Jia-Ling Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang City, Jiangxi Province 343000, China.
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Leng Q, Ding J, Dai M, Liu L, Fang Q, Wang DW, Wu L, Wang Y. Insights Into Platelet-Derived MicroRNAs in Cardiovascular and Oncologic Diseases: Potential Predictor and Therapeutic Target. Front Cardiovasc Med 2022; 9:879351. [PMID: 35757325 PMCID: PMC9218259 DOI: 10.3389/fcvm.2022.879351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/24/2022] [Indexed: 11/28/2022] Open
Abstract
Non-communicable diseases (NCDs), represented by cardiovascular diseases and cancer, have been the leading cause of death globally. Improvements in mortality from cardiovascular (CV) diseases (decrease of 14%/100,000, United States) or cancers (increase 7.5%/100,000, United States) seem unsatisfactory during the past two decades, and so the search for innovative and accurate biomarkers of early diagnosis and prevention, and novel treatment strategies is a valuable clinical and economic endeavor. Both tumors and cardiovascular system are rich in angiological systems that maintain material exchange, signal transduction and distant regulation. This pattern determines that they are strongly influenced by circulating substances, such as glycolipid metabolism, inflammatory homeostasis and cyclic non-coding RNA and so forth. Platelets, a group of small anucleated cells, inherit many mature proteins, mRNAs, and non-coding RNAs from their parent megakaryocytes during gradual formation and manifest important roles in inflammation, angiogenesis, atherosclerosis, stroke, myocardial infarction, diabetes, cancer, and many other diseases apart from its classical function in hemostasis. MicroRNAs (miRNAs) are a class of non-coding RNAs containing ∼22 nucleotides that participate in many key cellular processes by pairing with mRNAs at partially complementary binding sites for post-transcriptional regulation of gene expression. Platelets contain fully functional miRNA processors in their microvesicles and are able to transport their miRNAs to neighboring cells and regulate their gene expression. Therefore, the importance of platelet-derived miRNAs for the human health is of increasing interest. Here, we will elaborate systematically the roles of platelet-derived miRNAs in cardiovascular disease and cancer in the hope of providing clinicians with new ideas for early diagnosis and therapeutic strategies.
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Cognasse F, Duchez AC, Audoux E, Ebermeyer T, Arthaud CA, Prier A, Eyraud MA, Mismetti P, Garraud O, Bertoletti L, Hamzeh-Cognasse H. Platelets as Key Factors in Inflammation: Focus on CD40L/CD40. Front Immunol 2022; 13:825892. [PMID: 35185916 PMCID: PMC8850464 DOI: 10.3389/fimmu.2022.825892] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/14/2022] [Indexed: 12/16/2022] Open
Abstract
Platelets are anucleate cytoplasmic fragments derived from the fragmentation of medullary megakaryocytes. Activated platelets adhere to the damaged endothelium by means of glycoproteins on their surface, forming the platelet plug. Activated platelets can also secrete the contents of their granules, notably the growth factors contained in the α-granules, which are involved in platelet aggregation and maintain endothelial activation, but also contribute to vascular repair and angiogenesis. Platelets also have a major inflammatory and immune function in antibacterial defence, essentially through their Toll-like Receptors (TLRs) and Sialic acid-binding immunoglobulin-type lectin (SIGLEC). Platelet activation also contributes to the extensive release of anti- or pro-inflammatory mediators such as IL-1β, RANTES (Regulated on Activation, Normal T Expressed and Secreted) or CD154, also known as the CD40-ligand. Platelets are involved in the direct activation of immune cells, polynuclear neutrophils (PNNs) and dendritic cells via the CD40L/CD40 complex. As a general rule, all of the studies presented in this review show that platelets are capable of covering most of the stages of inflammation, primarily through the CD40L/CD40 interaction, thus confirming their own role in this pathophysiological condition.
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Affiliation(s)
- Fabrice Cognasse
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Anne Claire Duchez
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Estelle Audoux
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Theo Ebermeyer
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Charles Antoine Arthaud
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Amelie Prier
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Marie Ange Eyraud
- Etablissement Français du Sang Auvergne-Rhône-Alpes, Saint-Etienne, France.,SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Patrick Mismetti
- SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France.,Vascular and Therapeutic Medicine Department, Saint-Etienne University Hospital Center, Saint-Etienne, France
| | - Olivier Garraud
- SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France
| | - Laurent Bertoletti
- SAINBIOSE, INSERM, U1059, University of Lyon, Saint-Etienne, France.,Vascular and Therapeutic Medicine Department, Saint-Etienne University Hospital Center, Saint-Etienne, France
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Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Tsioufis K, Tousoulis D. Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches. Int J Mol Sci 2022; 23:3301. [PMID: 35328719 PMCID: PMC8955963 DOI: 10.3390/ijms23063301] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Platelets are at the forefront of human health and disease following the advances in their research presented in past decades. Platelet activation, their most crucial function, although beneficial in the case of vascular injury, may represent the initial step for thrombotic complications characterizing various pathologic states, primarily atherosclerotic cardiovascular diseases. In this review, we initially summarize the structural and functional characteristics of platelets. Next, we focus on the process of platelet activation and its associated factors, indicating the potential molecular mechanisms involving inflammation, endothelial dysfunction, and miRs. Finally, an overview of the available antiplatelet agents is being portrayed, together with agents possessing off-set platelet-inhibitory actions, while an extensive presentation of drugs under investigation is being given.
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Affiliation(s)
- Panagiotis Theofilis
- Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (E.O.); (A.S.A.); (K.T.)
| | - Marios Sagris
- Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (E.O.); (A.S.A.); (K.T.)
| | - Evangelos Oikonomou
- Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (E.O.); (A.S.A.); (K.T.)
- Cardiology Department, “Sotiria” Chest Diseases Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Alexios S. Antonopoulos
- Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (E.O.); (A.S.A.); (K.T.)
| | - Konstantinos Tsioufis
- Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (E.O.); (A.S.A.); (K.T.)
| | - Dimitris Tousoulis
- Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (E.O.); (A.S.A.); (K.T.)
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10
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Park SY, Lee SK, Lim M, Kim B, Hwang BO, Cho ES, Zhang X, Chun KS, Chung WY, Song NY. Direct Contact with Platelets Induces Podoplanin Expression and Invasion in Human Oral Squamous Cell Carcinoma Cells. Biomol Ther (Seoul) 2022; 30:284-290. [PMID: 35110423 PMCID: PMC9047494 DOI: 10.4062/biomolther.2021.167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/31/2021] [Accepted: 01/07/2022] [Indexed: 11/22/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is mostly diagnosed at an advanced stage, with local and/or distal metastasis. Thus, locoregional and/or local control of the primary tumor is crucial for a better prognosis in patients with OSCC. Platelets have long been considered major players in cancer metastasis. Traditional antiplatelet agents, such as aspirin, are thought to be potential chemotherapeutics, but they need to be used with caution because of the increased bleeding risk. Podoplanin (PDPN)-expressing cancer cells can activate platelets and promote OSCC metastasis. However, the reciprocal effect of platelets on PDPN expression in OSCC has not been investigated. In this study, we found that direct contact with platelets upregulated PDPN and integrin β1 at the protein level and promoted invasiveness of human OSCC Ca9.22 cells that express low levels of PDPN. In another human OSCC HSC3 cell line that express PDPN at an abundant level, silencing of the PDPN gene reduced cell invasiveness. Analysis of the public database further supported the co-expression of PDPN and integrin β1 and their increased expression in metastatic tissues compared to normal and tumor tissues of the oral cavity. Taken together, these data suggest that PDPN is a potential target to regulate platelet-tumor interaction and metastasis for OSCC treatment, which can overcome the limitations of traditional antiplatelet drugs.
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Affiliation(s)
- Se-Young Park
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 03722, Republic of Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Sun Kyoung Lee
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Mihwa Lim
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Bomi Kim
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Byeong-Oh Hwang
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 03722, Republic of Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Eunae Sandra Cho
- BK21 Four Project, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Xianglan Zhang
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Department of Pathology, Yanbian University Hospital, Yanji City, Jilin Province 133000, China
| | - Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Won-Yoon Chung
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 03722, Republic of Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
| | - Na-Young Song
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 03722, Republic of Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea
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11
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Hwang BO, Park SY, Cho ES, Zhang X, Lee SK, Ahn HJ, Chun KS, Chung WY, Song NY. Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment. Front Immunol 2022; 12:807600. [PMID: 34987523 PMCID: PMC8721674 DOI: 10.3389/fimmu.2021.807600] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/26/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis. Notably, cancer patients often show thrombocytosis, a status of an increased platelet number in the bloodstream, as well as the platelet infiltration into the tumor stroma, which contributes to cancer promotion and progression. Thus, platelets function as one of the important stromal components in the TME, emerging as a promising chemotherapeutic target. However, the use of traditional antiplatelet agents, such as aspirin, has limitations mainly due to increased bleeding complications. This requires to implement new strategies to target platelets for anti-cancer effects. In oral squamous cell carcinoma (OSCC) patients, both high platelet counts and low tumor-stromal ratio (high stroma) are strongly correlated with increased metastasis and poor prognosis. OSCC tends to invade adjacent tissues and bones and spread to the lymph nodes for distant metastasis, which is a huge hurdle for OSCC treatment in spite of relatively easy access for visual examination of precancerous lesions in the oral cavity. Therefore, locoregional control of the primary tumor is crucial for OSCC treatment. Similar to thrombocytosis, higher expression of podoplanin (PDPN) has been suggested as a predictive marker for higher frequency of lymph node metastasis of OSCC. Cumulative evidence supports that platelets can directly interact with PDPN-expressing cancer cells via C-type lectin-like receptor 2 (CLEC2), contributing to cancer cell invasion and metastasis. Thus, the platelet CLEC2-PDPN axis could be a pinpoint target to inhibit interaction between platelets and OSCC, avoiding undesirable side effects. Here, we will review the role of platelets in cancer, particularly focusing on CLEC2-PDPN interaction, and will assess their potentials as therapeutic targets for OSCC treatment.
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Affiliation(s)
- Byeong-Oh Hwang
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Se-Young Park
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Eunae Sandra Cho
- BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, South Korea.,Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea
| | - Xianglan Zhang
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Pathology, Yanbian University Hospital, Yanji City, China
| | - Sun Kyoung Lee
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Hyung-Joon Ahn
- Department of Orofacial Pain and Oral Medicine, Dental Hospital, Yonsei University College of Dentistry, Seoul, South Korea
| | - Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu, South Korea
| | - Won-Yoon Chung
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.,Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea
| | - Na-Young Song
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
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12
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Neubauer K, Zieger B. Role of Septins in Endothelial Cells and Platelets. Front Cell Dev Biol 2021; 9:768409. [PMID: 34858990 PMCID: PMC8632023 DOI: 10.3389/fcell.2021.768409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022] Open
Abstract
Septins are conserved cytoskeletal GTP-binding proteins identified in almost all eukaryotes except higher plants. Mammalian septins comprise 13 family members with either ubiquitous or organ- and tissue-specific expression patterns. They form filamentous oligomers and complexes with other proteins to serve as diffusions barrier and/or multi-molecular scaffolds to function in a physiologically regulated manner. Diverse septins are highly expressed in endothelial cells and platelets, which play an important role in hemostasis, a process to prevent blood loss after vascular injury. Endothelial septins are involved in cellular processes such as exocytosis and in processes concerning organismal level, like angiogenesis. Septins are additionally found in endothelial cell-cell junctions where their presence is required to maintain the integrity of the barrier function of vascular endothelial monolayers. In platelets, septins are important for activation, degranulation, adhesion, and aggregation. They have been identified as mediators of distinct platelet functions and being essential in primary and secondary hemostatic processes. Septin-knockout mouse studies show the relevance of septins in several aspects of hemostasis. This is in line with reports that dysregulation of septins is clinically relevant in human bleeding disorders. The precise function of septins in the biology of endothelial cells and platelets remains poorly understood. The following mini-review highlights the current knowledge about the role of septin cytoskeleton in regulating critical functions in these two cell types.
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Affiliation(s)
- Katharina Neubauer
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Barbara Zieger
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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13
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Mutua V, Gershwin LJ. A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clin Rev Allergy Immunol 2021; 61:194-211. [PMID: 32740860 PMCID: PMC7395212 DOI: 10.1007/s12016-020-08804-7] [Citation(s) in RCA: 358] [Impact Index Per Article: 89.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Activated neutrophils release neutrophil extracellular traps (NETs) in response to a variety of stimuli. NETosis is driven by protein-arginine deiminase type 4, with the release of intracellular granule components that function by capturing and destroying microbes, including viral, fungal, bacterial, and protozoal pathogens. The positive effects of pathogen control are countered by pro-inflammatory effects as demonstrated in a variety of diseases. Components of NETS are non-specific, and other than controlling microbes, they cause injury to surrounding tissue by themselves or by increasing the pro-inflammatory response. NETs can play a role in enhancement of the inflammation seen in autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosis. In addition, autoinflammatory diseases such as gout have been associated with NETosis. Inhibition of NETs may decrease the severity of many diseases improving survival. Herein, we describe NETosis in different diseases focusing on the detrimental effect of NETs and outline possible therapeutics that can be used to mitigate netosis. There is a need for more studies and clinical trials on these and other compounds that could prevent or destroy NETs, thereby decreasing damage to patients.
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Affiliation(s)
- Victoria Mutua
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, CA, USA.
| | - Laurel J Gershwin
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, CA, USA
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14
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Jeon BR, Irfan M, Lee SE, Lee JH, Rhee MH. Rumex acetosella Inhibits Platelet Function via Impaired MAPK and Phosphoinositide 3-Kinase Signaling. Chin J Integr Med 2021; 28:802-808. [PMID: 34546536 DOI: 10.1007/s11655-021-2873-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To examine the antiplatelet and antithrombotic activity of Rumex acetosella extract. METHODS Standard light aggregometry was used for platelet aggregation, intracellular calcium mobilization assessed using Fura-2/AM, granule secretion (ATP release) by luminometer, and fibrinogen binding to integrin αIIbβ3 detected using flow cytometry. Western blotting is carried out to determine the phosphorylation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling. RESULTS Rumex acetosella displayed the ability to inhibit platelet aggregation, calcium mobilization, granule secretion, and fibrinogen binding to integrin αIIbβ3. Rumex acetosella has also down-regulated MAPK and PI3K/Akt phosphorylation (all P<0.01). CONCLUSION Rumex acetosella extract exhibits antiplatelet activity via modulating GPVI signaling, and it may protect against the development of platelet-related cardiovascular diseases.
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Affiliation(s)
- Bo-Ra Jeon
- Laboratory of Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Muhammad Irfan
- Laboratory of Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Seung Eun Lee
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science (NIHHS), Eumseong, 27709, Republic of Korea
| | - Jeong Hoon Lee
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science (NIHHS), Eumseong, 27709, Republic of Korea
| | - Man Hee Rhee
- Laboratory of Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, Republic of Korea.
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15
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Andreeva T, Komsa-Penkova R, Langari A, Krumova S, Golemanov G, Georgieva GB, Taneva SG, Giosheva I, Mihaylova N, Tchorbanov A, Todinova S. Morphometric and Nanomechanical Features of Platelets from Women with Early Pregnancy Loss Provide New Evidence of the Impact of Inherited Thrombophilia. Int J Mol Sci 2021; 22:ijms22157778. [PMID: 34360543 PMCID: PMC8346153 DOI: 10.3390/ijms22157778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 11/25/2022] Open
Abstract
Pregnancy is associated with hypercoagulation states and increased thrombotic risk, especially in women with thrombophilia. We combine atomic force microscopy (AFM) and flow cytometry to examine the morphology and nanomechanics of platelets derived from women with early pregnancy loss (EPL) and control pregnant (CP) and non-pregnant (CNP) women. Both control groups exhibit similar morphometric parameters (height and surface roughness) and membrane stiffness of platelets. EPL patients’ platelets, on the other hand, are more activated than the control groups, with prominent cytoskeletal rearrangement. In particular, reduced membrane roughness (22.9 ± 6 nm vs. 39.1 ± 8 nm) (p < 0.05) and height (692 ± 128 nm vs. 1090 ± 131 nm) (p < 0.05), strong alteration in the membrane Young modulus, increased production of platelets’ microparticles, and higher expression of procoagulant surface markers, as well as increased occurrence of thrombophilia (FVL, FII20210A, PLA1/A2, MTHFR C677T or 4G/5G PAI-1) polymorphisms were found. We suggest that the carriage of thrombophilic mutations triggers structural and nanomechanical abnormalities in platelets, resulting in their increased activation. The activation state of platelets can be well characterized by AFM, and the morphometric and nanomechanical characteristics might serve as a new criterion for evaluation of the cause of miscarriage and offer the prospect of an innovative approach serving for diagnostic purposes.
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Affiliation(s)
- Tonya Andreeva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria; (T.A.); (A.L.); (S.K.); (S.G.T.); (I.G.)
| | - Regina Komsa-Penkova
- Department of Biochemistry, Medical University, 1 St. Kliment Ohridski Str., 5800 Pleven, Bulgaria; (R.K.-P.); (G.G.); (G.B.G.)
| | - Ariana Langari
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria; (T.A.); (A.L.); (S.K.); (S.G.T.); (I.G.)
| | - Sashka Krumova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria; (T.A.); (A.L.); (S.K.); (S.G.T.); (I.G.)
| | - Georgi Golemanov
- Department of Biochemistry, Medical University, 1 St. Kliment Ohridski Str., 5800 Pleven, Bulgaria; (R.K.-P.); (G.G.); (G.B.G.)
| | - Galya B. Georgieva
- Department of Biochemistry, Medical University, 1 St. Kliment Ohridski Str., 5800 Pleven, Bulgaria; (R.K.-P.); (G.G.); (G.B.G.)
| | - Stefka G. Taneva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria; (T.A.); (A.L.); (S.K.); (S.G.T.); (I.G.)
| | - Ina Giosheva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria; (T.A.); (A.L.); (S.K.); (S.G.T.); (I.G.)
- University Obstetrics and Gynecology Hospital “Maichin Dom”, 2 Zdrave Str., 1463 Sofia, Bulgaria
| | - Nikolina Mihaylova
- Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 26, 1113 Sofia, Bulgaria; (N.M.); (A.T.)
| | - Andrey Tchorbanov
- Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 26, 1113 Sofia, Bulgaria; (N.M.); (A.T.)
| | - Svetla Todinova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. Georgi Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria; (T.A.); (A.L.); (S.K.); (S.G.T.); (I.G.)
- Correspondence:
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16
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Tariq H, Perez Botero J, Higgins RA, Medina EA. Gray Platelet Syndrome Presenting With Pancytopenia, Splenomegaly, and Bone Marrow Fibrosis. Am J Clin Pathol 2021; 156:253-258. [PMID: 33586768 DOI: 10.1093/ajcp/aqaa229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Gray platelet syndrome (GPS) is a rare platelet storage pool disorder associated with a marked decrease or absence of platelet α-granules and their contents. It is characterized clinically by mild to moderate bleeding; moderate macrothrombocytopenia with large, agranular platelets; splenomegaly; and bone marrow fibrosis. Electron microscopy confirms markedly reduced or absent α-granules in platelets and megakaryocytes. The classic description of GPS is caused by homozygous mutations in NBEAL2 (neurobeachinlike 2). METHODS A 28-year-old Hispanic man with a history of easy bruising and occasional episodes of epistaxis sought treatment for pancytopenia and splenomegaly. Peripheral blood smear and bone marrow analysis, electron microscopy, and next-generation sequencing were performed. RESULTS Large and agranular platelets were present in the peripheral blood. There was bone marrow fibrosis. Electron microscopy of the platelets showed absence of α-granules. Next-generation sequencing revealed a germline apparently homozygous nonsense variant in the NBEAL2 gene: c.5674C>T, p.Gln1892X (p.Q1829X). CONCLUSIONS The differential diagnosis of GPS includes a myeloid neoplasm such as myelodysplastic syndrome with bone marrow fibrosis. The availability of diagnostic genetic panels for hereditable platelet disorders can assist in the recognition of GPS and other platelet disorders. We also describe a previously unreported pathogenic germline homozygous nonsense variant in the NBEAL2 gene: c.5674C>T, p.Gln1892X (p.Q1829X) in a patient with GPS.
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Affiliation(s)
- Hamza Tariq
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX, USA
| | | | - Russell A Higgins
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX, USA
| | - Edward A Medina
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX, USA
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Abstract
Endothelial cells form a monolayer, which lines blood vessels. They are crucially involved in maintaining blood fluidity and providing controlled vascular hemostasis at sites of injury. Thereby endothelial cells facilitate multiple mechanisms, including both procoagulant and anticoagulant, which must be kept in balance. Under physiological conditions, endothelial cells constitute a nonadhesive surface preventing activation of platelets and the coagulation cascade. Multiple fibrinolytic and antithrombotic properties act on their cell surface contributing to the maintenance of blood fluidity. These include platelet inhibition, the heparin-antithrombin III system, tissue factor pathway inhibition, thrombomodulin/protein C system, and fibrinolytic qualities. At sites of vascular damage, platelets react immediately by adhering to the exposed extracellular matrix, followed by platelet-platelet interactions to form a clot that effectively seals the injured vessel wall to prevent excessive blood loss. For solid thrombus formation, functional platelets are essential. In this process, endothelial cells serve as a support surface for formation of procoagulant complexes and clotting. This review gives an overview about the central role of the endothelium as a dynamic lining which controls the complex interplay of the coagulation system with the surrounding cells.
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Affiliation(s)
- Katharina Neubauer
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Barbara Zieger
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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18
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Anka Idrissi D, Senhaji N, Aouiss A, Khalki L, Tijani Y, Zaid N, Marhoume FZ, Naya A, Oudghiri M, Kabine M, Zaid Y. IL-1 and CD40/CD40L platelet complex: elements of induction of Crohn's disease and new therapeutic targets. Arch Pharm Res 2021; 44:117-132. [PMID: 33394309 DOI: 10.1007/s12272-020-01296-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 11/21/2020] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are chronic and multifactorial diseases that affect the intestinal tract, both characterized by recurrent inflammation of the intestinal mucosa, resulting in abdominal pain, diarrhea, vomiting and, rectal bleeding. Inflammatory bowel diseases (IBD) regroup these two disorders. The exact pathological mechanism of IBD remains ambiguous and poorly known. In genetically predisposed patients, defects in intestinal mucosal barrier are due to an uncontrolled inflammatory response to normal flora. In addition to the genetic predisposition, these defects could be triggered by environmental factors or by a specific lifestyle which is widely accepted as etiological hypothesis. The involvement of the CD40/CD40L platelet complex in the development of IBD has been overwhelmingly demonstrated. CD40L is climacteric in cell signalling in innate and adaptive immunity, the CD40L expression on the platelet cell surface gives them an immunological competence. The IL-1, a major inflammation mediator could be involved in different ways in the development of IBD. Here, we provide a comprehensive review regarding the role of platelet CD40/CD40L in the pathophysiological effect of IL-1 in the development of Crohn's disease (CD). This review could potentially help future approaches aiming to target these two pathways for therapeutic purposes and elucidate the immunological mechanisms driving gut inflammation.
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Affiliation(s)
- Doha Anka Idrissi
- Department of Biology, Faculty of Sciences, Hassan II University, Casablanca, Morocco
| | - Nezha Senhaji
- Laboratory of Genetic and Molecular Pathology, Faculty of Medicine, Hassan II University, Casablanca, Morocco
| | - Asmae Aouiss
- Department of Biology, Faculty of Sciences, Hassan II University, Casablanca, Morocco
| | - Loubna Khalki
- Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Youssef Tijani
- Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Nabil Zaid
- Faculty of Sciences, Department of Biology, Mohammed V University, Rabat, Morocco
| | - Fatima Zahra Marhoume
- Faculty of Sciences and Technology, Laboratory of Biochemistry and Neuroscience, Integrative and Computational Neuroscience Team, Hassan First University, Settat, Morocco
| | - Abdallah Naya
- Department of Biology, Faculty of Sciences, Hassan II University, Casablanca, Morocco
| | - Mounia Oudghiri
- Department of Biology, Faculty of Sciences, Hassan II University, Casablanca, Morocco
| | - Mostafa Kabine
- Department of Biology, Faculty of Sciences, Hassan II University, Casablanca, Morocco
| | - Younes Zaid
- Faculty of Sciences, Department of Biology, Mohammed V University, Rabat, Morocco. .,Research Center of Abulcasis, University of Health Sciences, Rabat, Morocco.
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19
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Sheriff J, Malone LE, Avila C, Zigomalas A, Bluestein D, Bahou WF. Shear-Induced Platelet Activation is Sensitive to Age and Calcium Availability: A Comparison of Adult and Cord Blood. Cell Mol Bioeng 2020; 13:575-590. [PMID: 33281988 PMCID: PMC7704822 DOI: 10.1007/s12195-020-00628-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 06/16/2020] [Indexed: 10/24/2022] Open
Abstract
INTRODUCTION Antiplatelet therapy for neonates and infants is often extrapolated from the adult experience, based on limited observation of agonist-induced neonatal platelet hypoactivity and poor understanding of flow shear-mediated platelet activation. Therefore, thrombotic events due to device-associated disturbed flow are inadequately mitigated in critically ill neonates with indwelling umbilical catheters and infants receiving cardiovascular implants. METHODS Whole blood (WB), platelet-rich plasma (PRP), and gel-filtered platelets (GFP) were prepared from umbilical cord and adult blood, and exposed to biochemical agonists or pathological shear stress of 70 dyne/cm2. We evaluated α-granule release, phosphatidylserine (PS) scrambling, and procoagulant response using P-selectin expression, Annexin V binding, and thrombin generation (PAS), respectively. Activation modulation due to depletion of intracellular and extracellular calcium, requisite second messengers, was also examined. RESULTS Similar P-selectin expression was observed for sheared adult and cord platelets, with concordant inhibition due to intracellular and extracellular calcium depletion. Sheared cord platelet Annexin V binding and PAS activity was similar to adult values in GFP, but lower in PRP and WB. Annexin V on sheared cord platelets was calcium-independent, with PAS slightly reduced by intracellular calcium depletion. CONCLUSIONS Increased PS activity on purified sheared cord platelets suggest that their intrinsic function under pathological flow conditions is suppressed by cell-cell or plasmatic components. Although secretory functions of adult and cord platelets retain comparable calcium-dependence, PS exposure in sheared cord platelets is uniquely calcium-independent and distinct from adults. Identification of calcium-regulated developmental disparities in shear-mediated platelet function may provide novel targets for age-specific antiplatelet therapy.
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Affiliation(s)
- Jawaad Sheriff
- Department of Biomedical Engineering, T08-50 Health Sciences Center, Stony Brook University, Stony Brook, NY 11794-8084 USA
| | - Lisa E. Malone
- Division of Hematology and Oncology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794 USA
| | - Cecilia Avila
- Department of Obstetrics, Gynecology and Reproductive Medicine, Stony Brook University, Stony Brook, NY 11794 USA
| | - Amanda Zigomalas
- Department of Biomedical Engineering, T08-50 Health Sciences Center, Stony Brook University, Stony Brook, NY 11794-8084 USA
| | - Danny Bluestein
- Department of Biomedical Engineering, T08-50 Health Sciences Center, Stony Brook University, Stony Brook, NY 11794-8084 USA
| | - Wadie F. Bahou
- Division of Hematology and Oncology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794 USA
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Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
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Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
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Purification and characterization of non-enzymatic glycoprotein (NEGp) from flax seed buffer extract that exhibits anticoagulant and antiplatelet activity. Int J Biol Macromol 2020; 163:317-326. [PMID: 32629053 DOI: 10.1016/j.ijbiomac.2020.06.270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 06/29/2020] [Accepted: 06/29/2020] [Indexed: 12/25/2022]
Abstract
The current study deals with the purification and characterization of non-enzymatic glycoprotein (NEGp) from flax seed buffer extract. Sephadex G-100 and DEAE-A25 column chromatography techniques were employed to isolate NEGp. NEGp showed single sharp band at 29 kDa region on 10% SDS-PAGE, and under reduced and non-reduced conditions revealed its monomeric nature. Besides, NEGp taken up the PAS stain at 29 kDa region reveals the presence of carbohydrate moiety. Purity of NEGp was adjudged by RP-HPLC, as it revealed a single sharp peak at the retention time of 3.4 min. The exact molecular mass of NEGp was found to be 26 kDa which was confirmed by MALDI-TOF. Circular di-chromism spectra of NEGp showed 12.0% α-helix, 24.3% α-helix turn and 63.7% random coils without beta pleated sheets. NEGp was found to exhibit anticoagulant activity by extending clotting time of both platelet rich plasma and platelet poor plasma from control 240 s to 1800 s and 280 s to 2100 s respectively at the concentration of 8 μg. NEGp inhibited the agonists such as ADP, epinephrine and arachidonic acid induced platelet aggregation in washed platelets. The percentage of inhibition was found to be 70%, 80% and 60% respectively. While, it did not interfere in thrombin, PAF and collagen induced platelet aggregation. NEGp did not hydrolyse RBC membrane, devoid of haemorrhagic and edema inducing properties in experimental mice.
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22
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Thibeault PE, Ramachandran R. Biased signaling in platelet G-protein coupled receptors. Can J Physiol Pharmacol 2020; 99:255-269. [PMID: 32846106 DOI: 10.1139/cjpp-2020-0149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Platelets are small megakaryocyte-derived, anucleate, disk-like structures that play an outsized role in human health and disease. Both a decrease in the number of platelets and a variety of platelet function disorders result in petechiae or bleeding that can be life threatening. Conversely, the inappropriate activation of platelets, within diseased blood vessels, remains the leading cause of death and morbidity by affecting heart attacks and stroke. The fine balance of the platelet state in healthy individuals is controlled by a number of receptor-mediated signaling pathways that allow the platelet to rapidly respond and maintain haemostasis. G-protein coupled receptors (GPCRs) are particularly important regulators of platelet function. Here we focus on the major platelet-expressed GPCRs and discuss the roles of downstream signaling pathways (e.g., different G-protein subtypes or β-arrestin) in regulating the different phases of the platelet activation. Further, we consider the potential for selectively targeting signaling pathways that may contribute to platelet responses in disease through development of biased agonists. Such selective targeting of GPCR-mediated signaling pathways by drugs, often referred to as biased signaling, holds promise in delivering therapeutic interventions that do not present significant side effects, especially in finely balanced physiological systems such as platelet activation in haemostasis.
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Affiliation(s)
- Pierre E Thibeault
- Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street, London, ON N6A5C1, Canada.,Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street, London, ON N6A5C1, Canada
| | - Rithwik Ramachandran
- Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street, London, ON N6A5C1, Canada.,Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street, London, ON N6A5C1, Canada
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23
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Arctigenin attenuates platelet activation and clot retraction by regulation of thromboxane A 2 synthesis and cAMP pathway. Biomed Pharmacother 2020; 130:110535. [PMID: 32707441 DOI: 10.1016/j.biopha.2020.110535] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 11/22/2022] Open
Abstract
Pathophysiological reaction of platelets in the blood vessel is an indispensable part of thrombosis and cardiovascular disease, which is the most common cause of death in the world. In this study, we performed in vitro assays to evaluate antiplatelet activity of arctigenin in human platelets and attempted to identify the mechanism responsible for thromboxane A2 (TXA2) generation, integrin αIIbβ3 activation and cAMP pathway. Arctigenin exhibited obvious inhibitory effects on collagen-, thrombin-, and ADP-induced human platelet aggregation, granule secretion, TXA2 generation, integrin αIIbβ3 activation, and clot retraction. Additionally, we found that arctigenin attenuated PI3K/Akt/mTOR/GSK-3β and MAPK signaling pathways, and increased cAMP level. Accordingly, the findings support that arctigenin attenuates thrombotic events through the inhibition of platelet activation and platelet plug formation. Therefore, we suggest that arctigenin may have therapeutic potential as an antiplatelet and antithrombotic agent.
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24
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Lordan R, Tsoupras A, Zabetakis I. Platelet activation and prothrombotic mediators at the nexus of inflammation and atherosclerosis: Potential role of antiplatelet agents. Blood Rev 2020; 45:100694. [PMID: 32340775 DOI: 10.1016/j.blre.2020.100694] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 03/22/2020] [Accepted: 04/07/2020] [Indexed: 12/20/2022]
Abstract
Platelets are central to inflammation-related manifestations of cardiovascular diseases (CVD) such as atherosclerosis. Platelet-activating factor (PAF), thrombin, thromboxane A2 (TxA2), and adenosine diphosphate (ADP) are some of the key agonists of platelet activation that are at the intersection between a plethora of inflammatory pathways that modulate pro-inflammatory and coagulation processes. The aim of this article is to review the role of platelets and the relationship between their structure, function, and the interactions of their constituents in systemic inflammation and atherosclerosis. Antiplatelet therapies are discussed with a view to primary prevention of CVD by the clinical reduction of platelet reactivity and inflammation. Current antiplatelet therapies are effective in reducing cardiovascular risk but increase bleeding risk. Novel therapeutic antiplatelet approaches beyond current pharmacological modalities that do not increase the risk of bleeding require further investigation. There is potential for specifically designed nutraceuticals that may become safer alternatives to pharmacological antiplatelet agents for the primary prevention of CVD but there is serious concern over their efficacy and regulation, which requires considerably more research.
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Affiliation(s)
- Ronan Lordan
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute (HRI), University of Limerick, Limerick, Ireland; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5158, USA.
| | - Alexandros Tsoupras
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute (HRI), University of Limerick, Limerick, Ireland
| | - Ioannis Zabetakis
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute (HRI), University of Limerick, Limerick, Ireland
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25
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Zhuang M, Song M, Liu D, Huang J, Sun B. Exogenous carbon monoxide suppresses LPS-Induced platelet SNAREs complex assembly and α-granule exocytosis via integrin αIIbβ3-Mediated PKCθ/Munc18a pathway. Exp Cell Res 2020; 386:111735. [PMID: 31751554 DOI: 10.1016/j.yexcr.2019.111735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/08/2019] [Accepted: 11/16/2019] [Indexed: 12/01/2022]
Abstract
Activation of coagulation occurs in sepsis and contributes to the development of thrombosis. Platelet α-granule exocytosis plays an important role in septic coagulation abnormalities. The present study aimed to investigate the effects and the underlying mechanisms of exogenous carbon monoxide, carbon monoxide-releasing molecules II (CORM-2)-liberated CO, on suppressing platelet α-granule exocytosis in sepsis. It was shown that CORM-2 weakened α-granule membrane fusion with platelet plasma membrane and attenuated α-granule contents exocytosis in LPS-Induced platelet. Further studies revealed that CORM-2 suppressed the expression of integrin αIIbβ3 in platelets stimulated by LPS. This was accompanied by a decrease in production and phosphorylation of PKCθ and Munc18a, SNARE complex assembly and subsequently platelet α-granule exocytosis. Taken together, we suggested that the potential mechanism of suppressive effect of CORM-2 on LPS-induced platelet SNAREs complex assembly and α-Granule Exocytosis might involve integrin αIIbβ3-mediated PKCθ/Munc18a pathway activation.
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Affiliation(s)
- Mingfeng Zhuang
- Department of Burns and Plastic Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China; Intensive Care Medicine, Jiangyin People's Hospital, Jiangyin, 214400, Jiangsu Province, China
| | - Mingming Song
- Department of Burns and Plastic Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China
| | - Dadong Liu
- Department of Burns and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Jiamin Huang
- Department of Burns and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Bingwei Sun
- Department of Burns and Plastic Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China.
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26
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Nam GS, Lee KS, Nam KS. Anti‑platelet activity of mineral‑balanced deep sea water is mediated via the regulation of Akt and ERK pathway crosstalk. Int J Mol Med 2020; 45:658-668. [PMID: 31894254 DOI: 10.3892/ijmm.2019.4424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 11/14/2019] [Indexed: 11/06/2022] Open
Abstract
Mineral‑balanced deep sea water (MBDSW), an unlimited natural sea source, has been demonstrated to minimize the risk of developing cardiovascular diseases, such as obesity, hypertension, inflammation and hyperlipidemia. This study investigated the effects of MBDSW [magnesium (Mg):calcium (Ca) ratio, 3:1] on platelet activation. MBDSW significantly inhibited the collagen‑ and thrombin‑induced platelet aggregation of human platelets. In collagen‑induced platelets, MBDSW inhibited intracellular calcium mobilization, granule secretion [serotonin, adenosine triphosphate (ATP) and P‑selectin expression] and thromboxane A2 (TXA2) production. Moreover, MBDSW markedly inhibited Akt and extracellular signal‑regulated kinase (ERK) phosphorylation, but not that of c‑Jun N‑terminal kinase (JNK) and p38. Moreover, MBDSW phosphorylated inositol 1,4,5‑triphosphate receptor (IP3R) and vasodilator‑stimulated phosphoprotein (VASP), and it increased the cyclic adenosine monophosphate (cAMP) level in collagen‑induced human platelets. Dipyridamole, a phosphodiesterase (PDE) inhibitor, significantly increased the cAMP level and regulated the Akt, ERK and VASP (Ser157) levels in a manner similar to that of MBDSW. In addition, LY294002, an Akt inhibitor, inhibited the phosphorylation of ERK, and U0126, an ERK inhibitor, inhibited the phosphorylation of Akt. Taken together, the results of the present investigation suggest that the inhibitory effects of MBDSW on platelet aggregation may be associated with the cross‑inhibition of Akt and ERK phosphorylation. These results strongly indicate that MBDSW may have preventive or therapeutic potential for platelet aggregation‑mediated diseases, such as thrombosis, atherosclerosis and myocardial infarction.
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Affiliation(s)
- Gi Suk Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk‑do 38066, Republic of Korea
| | - Kyu-Shik Lee
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk‑do 38066, Republic of Korea
| | - Kyung-Soo Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk‑do 38066, Republic of Korea
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27
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Ramirez GA, Manfredi AA, Maugeri N. Misunderstandings Between Platelets and Neutrophils Build in Chronic Inflammation. Front Immunol 2019; 10:2491. [PMID: 31695699 PMCID: PMC6817594 DOI: 10.3389/fimmu.2019.02491] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 10/07/2019] [Indexed: 12/14/2022] Open
Abstract
Regulated hemostasis, inflammation and innate immunity entail extensive interactions between platelets and neutrophils. Under physiological conditions, vascular inflammation offers a template for the establishment of effective intravascular immunity, with platelets providing neutrophils with an array of signals that increase their activation threshold, thus limiting collateral damage to tissues and promoting termination of the inflammatory response. By contrast, persistent systemic inflammation as observed in immune-mediated diseases, such as systemic vasculitides, systemic sclerosis, systemic lupus erythematosus or rheumatoid arthritis is characterized by platelet and neutrophil reciprocal activation, which ultimately culminates in the generation of thrombo-inflammatory lesions, fostering vascular injury and organ damage. Here, we discuss recent evidence regarding the multifaceted aspects of platelet-neutrophil interactions from bone marrow precursors to shed microparticles. Moreover, we analyse shared and disease-specific events due to an aberrant deployment of these interactions in human diseases. To restore communications between the pillars of the immune-hemostatic continuum constitutes a fascinating challenge for the near future.
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Affiliation(s)
- Giuseppe A Ramirez
- Vita-Salute San Raffaele University, Milan, Italy.,Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Angelo A Manfredi
- Vita-Salute San Raffaele University, Milan, Italy.,Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Norma Maugeri
- Vita-Salute San Raffaele University, Milan, Italy.,Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
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28
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Nam GS, Lee KS, Nam KS. Morin hydrate inhibits platelet activation and clot retraction by regulating integrin α IIbβ 3, TXA 2, and cAMP levels. Eur J Pharmacol 2019; 865:172734. [PMID: 31614139 DOI: 10.1016/j.ejphar.2019.172734] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/10/2019] [Accepted: 10/11/2019] [Indexed: 01/27/2023]
Abstract
Morin hydrate is an active constituent of Morus alba L, Prunus dulcis, and Cudrania tricuspidata and has been reported to inhibit platelet activation in vivo and in vitro, but no reports have been issued on its regulation of αIIbβ3, a platelet-specific integrin and thromboxane A2 (TXA2), positive feedback molecule. In this study, we investigated the anti-platelet activity of morin hydrate in collagen- and thrombin-induced human platelets and attempted to identify the mechanism responsible for integrin αIIbβ3 activation and TXA2 generation. Our results demonstrated that morin hydrate (25-100 μM) inhibited collagen- and thrombin-induced platelet aggregation, granule secretion (P-selectin expression, ATP, and serotonin release), calcium mobilization, TXA2 production, integrin αIIbβ3 activation, and clot retraction. Additionally, morin hydrate attenuated the phosphorylations of phospholipase Cγ2 (PLCγ2), cytosolic phospholipase A2 (cPLA2), phosphoinositide 3-kinase (PI3K), Akt, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), and enhanced the phosphorylations of inositol trisphosphate receptor (IP3 receptor) and cyclic adenosine monophosphate (cAMP) generation. However, it had no effect on the coagulation pathway. Taken together, these observations indicate morin hydrate inhibits platelet-mediated thrombosis by down-regulating TXA2 production and integrin αIIbβ3 activation, and by upregulating cAMP generation, and thus, inhibits clot retraction. These results suggest morin hydrate may have therapeutic potential as a treatment for platelet-activation-related diseases.
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Affiliation(s)
- Gi Suk Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do, 38066, Republic of Korea
| | - Kyu-Shik Lee
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do, 38066, Republic of Korea
| | - Kyung-Soo Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do, 38066, Republic of Korea.
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29
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Ravishankar D, Albadawi DAI, Chaggar V, Patra PH, Williams HF, Salamah M, Vaiyapuri R, Dash PR, Patel K, Watson KA, Vaiyapuri S. Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation. Eur J Pharmacol 2019; 862:172627. [PMID: 31461638 DOI: 10.1016/j.ejphar.2019.172627] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 08/17/2019] [Accepted: 08/23/2019] [Indexed: 12/13/2022]
Abstract
Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.
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Affiliation(s)
| | | | | | | | | | | | | | - Philip R Dash
- School of Biological Sciences, University of Reading, Reading, UK
| | - Ketan Patel
- School of Biological Sciences, University of Reading, Reading, UK
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30
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Bandyopadhyay SK, Azharuddin M, Dasgupta AK, Ganguli B, SenRoy S, Patra HK, Deb S. Probing ADP Induced Aggregation Kinetics During Platelet-Nanoparticle Interactions: Functional Dynamics Analysis to Rationalize Safety and Benefits. Front Bioeng Biotechnol 2019; 7:163. [PMID: 31380358 PMCID: PMC6657536 DOI: 10.3389/fbioe.2019.00163] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 06/20/2019] [Indexed: 11/13/2022] Open
Abstract
Platelets, one of the most sensitive blood cells, can be activated by a range of external and internal stimuli including physical, chemical, physiological, and/or non-physiological agents. Platelets need to respond promptly during injury to maintain blood hemostasis. The time profile of platelet aggregation is very complex, especially in the presence of the agonist adenosine 5'-diphosphate (ADP), and it is difficult to probe such complexity using traditional linear dose response models. In the present study, we explored functional analysis techniques to characterize the pattern of platelet aggregation over time in response to nanoparticle induced perturbations. This has obviated the need to represent the pattern of aggregation by a single summary measure and allowed us to treat the entire aggregation profile over time, as the response. The modeling was performed in a flexible manner, without any imposition of shape restrictions on the curve, allowing smooth platelet aggregation over time. The use of a probabilistic framework not only allowed statistical prediction and inference of the aggregation signatures, but also provided a novel method for the estimation of higher order derivatives of the curve, thereby allowing plausible estimation of the extent and rate of platelet aggregation kinetics over time. In the present study, we focused on the estimated first derivative of the curve, obtained from the platelet optical aggregometric profile over time and used it to discern the underlying kinetics as well as to study the effects of ADP dosage and perturbation with gold nanoparticles. In addition, our method allowed the quantification of the extent of inter-individual signature variations. Our findings indicated several hidden features and showed a mixture of zero and first order kinetics interrupted by a metastable zero order ADP dose dependent process. In addition, we showed that the two first order kinetic constants were ADP dependent. However, we were able to perturb the overall kinetic pattern using gold nanoparticles, which resulted in autocatalytic aggregation with a higher aggregate mass and which facilitated the aggregation rate.
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Affiliation(s)
| | - Mohammad Azharuddin
- Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden
| | - Anjan K Dasgupta
- Department of Biochemistry, University of Calcutta, Kolkata, India
| | - Bhaswati Ganguli
- Department of Statistics, University of Calcutta, Kolkata, India
| | - Sugata SenRoy
- Department of Statistics, University of Calcutta, Kolkata, India
| | - Hirak K Patra
- Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.,Wolfson College, University of Cambridge, Cambridge, United Kingdom.,Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
| | - Suryyani Deb
- Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, Kolkata, India
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31
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Mitrugno A, Rigg RA, Laschober NB, Ngo AT, Pang J, Williams CD, Aslan JE, McCarty OJ. Potentiation of TRAP-6-induced platelet dense granule release by blockade of P2Y 12 signaling with MRS2395. Platelets 2018; 29:383-394. [PMID: 28523947 PMCID: PMC6155984 DOI: 10.1080/09537104.2017.1316482] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/06/2017] [Accepted: 03/24/2017] [Indexed: 12/30/2022]
Abstract
The release of ADP from platelet dense granules and its binding to platelet P2Y12 receptors is key to amplifying the initial hemostatic response and propagating thrombus formation. P2Y12 has thus emerged as a therapeutic target to safely and effectively prevent secondary thrombotic events in patients with acute coronary syndrome or a history of myocardial infarction. Pharmacological inhibition of P2Y12 receptors represents a useful approach to better understand the signaling mediated by these receptors and to elucidate the role of these receptors in a multitude of platelet hemostatic and thrombotic responses. The present work examined and compared the effects of four different P2Y12 inhibitors (MRS2395, ticagrelor, PSB 0739, and AR-C 66096) on platelet function in a series of in vitro studies of platelet dense granule secretion and trafficking, calcium generation, and protein phosphorylation. Our results show that in platelets activated with the PAR-1 agonist TRAP-6 (thrombin receptor-activating peptide), inhibition of P2Y12 with the antagonist MRS2395, but not ticagrelor, PSB 0739 or AR-C 66096, potentiated human platelet dense granule trafficking to the plasma membrane and release into the extracellular space, cytosolic Ca2+ influx, and phosphorylation of GSK3β-Ser9 through a PKC-dependent pathway. These results suggest that inhibition of P2Y12 with MRS2395 may act in concert with PAR-1 signaling and result in the aberrant release of ADP by platelet dense granules, thus reducing or counteracting the anticipated anti-platelet efficacy of this inhibitor.
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Affiliation(s)
- Annachiara Mitrugno
- Department of Biomedical Engineering,Oregon Health & Science University, Portland, OR, USA
- Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
- Division of Hematology & Medical Oncology and Oregon Health & Science University, Portland, OR,
USA
| | - Rachel A. Rigg
- Department of Biomedical Engineering,Oregon Health & Science University, Portland, OR, USA
| | - Nicole B. Laschober
- Department of Biomedical Engineering,Oregon Health & Science University, Portland, OR, USA
| | - Anh T.P. Ngo
- Department of Biomedical Engineering,Oregon Health & Science University, Portland, OR, USA
| | - Jiaqing Pang
- Department of Biomedical Engineering,Oregon Health & Science University, Portland, OR, USA
| | | | - Joseph E. Aslan
- Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR,
USA
| | - Owen J.T. McCarty
- Department of Biomedical Engineering,Oregon Health & Science University, Portland, OR, USA
- Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
- Division of Hematology & Medical Oncology and Oregon Health & Science University, Portland, OR,
USA
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32
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Wang S, Jiang T, Fan Y, Zhao S. A proteomic approach reveals the variation in human platelet protein composition after storage at different temperatures. Platelets 2018; 30:403-412. [PMID: 29595346 DOI: 10.1080/09537104.2018.1453060] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cryopreservation can slow down the metabolism and decrease the risk of bacterial contamination. But, chilled platelets (PLTs) show a reduced period in circulation due to the rapid clearance by hepatic cells or spleen macrophages after transfusion. The deleterious changes that PLTs undergo are mainly considered the result of PLT protein variation. However, the basis for proteomic variation of stored PLTs remains poorly understood. Besides count, activation markers (CD62P and Annexin V), and aggregation, we used quantitative mass spectrometry to create the first comprehensive and quantitative human PLT proteome of samples stored at different temperatures (22°C, 10°C and -80°C). We found different conditions caused different platelet storage lesion (PSL). PLT count was decreased no matter at what temperature stored. PLTs viability at low temperature dropped by 21.78% and 11.21%, respectively, as compared 10.26% at room temperature, there were no significant differences between the storage methods. Membrane expression of CD62P gradually increased in all groups especially stored at 22°C up to 40% and 10°C up to 30%. However, exposure of PS on the PLT membrane was below 1% in every group. The PLT proteome showed there were 575 and 454 potential proteins identified by general iTRAQ analysis and phosphorylation iTRAQ a nalysis, respectively, among them, 33 common differentially expressed proteins caused by storage time and 44 caused by storage temperature Especially, membrane-bound proteins (such as FERMT3, STX4, MYL9 and TAGLN2) played key roles in PLT storage lesion. The pathways "Endocytosis", "Fc gamma R-mediated phagocytosis" and "Regulation of actin cytoskeleton" were affected predominantly by storage time. And the pathways "SNARE interactions in vesicular transport" and "Vasopressin-regulated water reabsorption" were affected by cold storage in our study. Proteomic results can help us to understand PLT biochemistry and physiology and thus unravel the mechanisms of PSL in time and space for more successful PLT transfusion therapy.
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Affiliation(s)
- Shichun Wang
- a Department of Blood Transfusion , Southwest Hospital, the Third Military Medical University , Chongqing , P.R. China
| | - Tianlun Jiang
- a Department of Blood Transfusion , Southwest Hospital, the Third Military Medical University , Chongqing , P.R. China
| | - Yahan Fan
- a Department of Blood Transfusion , Southwest Hospital, the Third Military Medical University , Chongqing , P.R. China
| | - Shuming Zhao
- a Department of Blood Transfusion , Southwest Hospital, the Third Military Medical University , Chongqing , P.R. China
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33
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Hsia CH, Jayakumar T, Sheu JR, Tsao SY, Velusamy M, Hsia CW, Chou DS, Chang CC, Chung CL, Khamrang T, Lin KC. Structure-Antiplatelet Activity Relationships of Novel Ruthenium (II) Complexes: Investigation of Its Molecular Targets. Molecules 2018; 23:molecules23020477. [PMID: 29470443 PMCID: PMC6017231 DOI: 10.3390/molecules23020477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 02/14/2018] [Accepted: 02/19/2018] [Indexed: 01/02/2023] Open
Abstract
The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study. Of the three tested compounds, TQ-3 showed a concentration (1–5 μM) dependent inhibitory effect on platelet aggregation induced by collagen (1 μg/mL) and thrombin (0.01 U/mL) in washed human platelets; however, TQ-1 and TQ-2 had no response even at 250 μM of collagen and thrombin-induced aggregation. TQ-3 was effective with inhibiting collagen-induced ATP release, calcium mobilization ([Ca2+]i) and P-selectin expression without cytotoxicity. Moreover, TQ-3 significantly abolished collagen-induced Lyn-Fyn-Syk, Akt-JNK and p38 mitogen-activated protein kinases (p38 MAPKs) phosphorylation. The compound TQ-3 containing an electron donating amino group with two phenyl groups of the quinoline core could be accounted for by its hydrophobicity and this nature might be the reason for the noted antiplatelet effects of TQ-3. The present results provide a molecular basis for the inhibition by TQ-3 in collagen-induced platelet aggregation, through the suppression of multiple machineries of the signaling pathway. These results may suggest that TQ-3 can be considered a potential agent for the treatment of vascular diseases.
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Affiliation(s)
- Chih-Hsuan Hsia
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Thanasekaran Jayakumar
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Joen-Rong Sheu
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Shin-Yi Tsao
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei 22174, Taiwan.
| | - Marappan Velusamy
- Department of Chemistry, North Eastern Hill University, Shillong 793022, India.
| | - Chih-Wei Hsia
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Duen-Suey Chou
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Chao-Chien Chang
- Department of Cardiology, Cathay General Hospital, Taipei 106, Taiwan.
| | - Chi-Li Chung
- Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 106, Taiwan.
| | - Themmila Khamrang
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Chemistry, North Eastern Hill University, Shillong 793022, India.
| | - Kao-Chang Lin
- Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
- Department of Neurology, Chi Mei Medical Center, Tainan 710, Taiwan.
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34
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Selvadurai MV, Hamilton JR. Structure and function of the open canalicular system – the platelet’s specialized internal membrane network. Platelets 2018; 29:319-325. [DOI: 10.1080/09537104.2018.1431388] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Maria V. Selvadurai
- Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
| | - Justin R. Hamilton
- Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
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35
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Abstract
PURPOSE OF REVIEW The present review will provide an overview of several recent advances in the field of vascular thiol isomerase function. RECENT FINDINGS The initial observation that protein disulfide isomerase (PDI) functions in thrombus formation occurred approximately a decade ago. At the time, there was little understanding regarding how PDI or other vascular thiol isomerases contribute to thrombosis. Although this problem is far from solved, the past few years have seen substantial progress in several areas that will be reviewed in this article. The relationship between PDI structure and its function has been investigated and applied to identify domains of PDI that are critical for thrombus formation. The mechanisms that direct thiol isomerase storage and release from platelets and endothelium have been studied. New techniques including kinetic-based trapping have identified substrates that vascular thiol isomerases modify during thrombus formation. Novel inhibitors of thiol isomerases have been developed that are useful both as tools to interrogate PDI function and as potential therapeutics. Human studies have been conducted to measure circulating PDI in disease states and evaluate the effect of oral administration of a PDI inhibitor on ex-vivo thrombin generation. SUMMARY Current findings indicate that thiol isomerase-mediated disulfide bond modification in receptors and plasma proteins is an important layer of control of thrombosis and vascular function more generally.
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36
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Tsai HJ, Chien KY, Liao HR, Shih MS, Lin YC, Chang YW, Cheng JC, Tseng CP. Functional links between Disabled-2 Ser723 phosphorylation and thrombin signaling in human platelets. J Thromb Haemost 2017; 15:2029-2044. [PMID: 28876503 DOI: 10.1111/jth.13785] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Indexed: 01/17/2023]
Abstract
Essentials Disabled-2 (Dab2) phosphorylation status in thrombin signaling of human platelet was investigated. Ser723 was the major Dab2 phosphorylation site in human platelets stimulated by thrombin. Dab2 S723 phosphorylation (pS723) caused the dissociation of Dab2-CIN85 protein complex. Dab2-pS723 regulated ADP release and integrin αIIbβ3 activation in thrombin-treated platelets. SUMMARY Background Disabled-2 (Dab2) is a platelet protein that is functionally involved in thrombin signaling in mice. It is unknown whether or not Dab2 undergoes phosphorylation during human platelet activation. Objectives To investigate the phosphorylation status of Dab2 and its functional consequences in thrombin-stimulated human platelets. Methods Dab2 was immunoprecipitated from resting and thrombin-stimulated platelet lysates for differential isotopic labeling. After enrichment of the phosphopeptides, the phosphorylation sites were analyzed by mass spectrometry. The corresponding phospho-specific antibody was generated. The protein kinases responsible for and the functional significance of Dab2 phosphorylation were defined by the use of signaling pathway inhibitors/activators, protein kinase assays, and various molecular approaches. Results Dab2 was phosphorylated at Ser227, Ser394, Ser401 and Ser723 in thrombin-stimulated platelets, with Ser723 phosphorylation being the most significantly increased by thrombin. Dab2 was phosphorylated by protein kinase C at Ser723 in a Gαq -dependent manner. ADP released from the stimulated platelets further activated the Gβγ -dependent pathway to sustain Ser723 phosphorylation. The Cbl-interacting protein of 85 kDa (CIN85) bound to Dab2 at a motif adjacent to Ser723 in resting platelets. The consequence of Ser723 phosphorylation was the dissociation of CIN85 from the Dab2-CIN85 complex. These molecular events led to increases in fibrinogen binding and platelet aggregation in thrombin-stimulated platelets by regulating αIIb β3 activation and ADP release. Conclusions Dab2 Ser723 phosphorylation is a key molecular event in thrombin-stimulated inside-out signaling and platelet activation, contributing to a new function of Dab2 in thrombin signaling.
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Affiliation(s)
- H-J Tsai
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - K-Y Chien
- Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Clinical Proteomics Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - H-R Liao
- Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - M-S Shih
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Y-C Lin
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Y-W Chang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - J-C Cheng
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, China Medical University, Taichung, Taiwan
| | - C-P Tseng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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37
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Sekhon UDS, Sen Gupta A. Platelets and Platelet-Inspired Biomaterials Technologies in Wound Healing Applications. ACS Biomater Sci Eng 2017; 4:1176-1192. [DOI: 10.1021/acsbiomaterials.7b00013] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ujjal Didar Singh Sekhon
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44102, United States
| | - Anirban Sen Gupta
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44102, United States
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38
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Stereochemistry- and concentration-dependent effects of phosphatidylserine enrichment on platelet function. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1859:1381-1387. [PMID: 28472616 DOI: 10.1016/j.bbamem.2017.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 03/15/2017] [Accepted: 04/28/2017] [Indexed: 11/20/2022]
Abstract
Platelets are small (1-2μm in diameter), circulating anuclear cell fragments with important roles in hemostasis and thrombosis that provide an excellent platform for studying the role of membrane components in cellular communication. Platelets use several forms of communication including exocytosis of three distinct granule populations, formation of bioactive lipid mediators, and shape change (allowing for adhesion). This work explores the role of stereochemistry and concentration of exogenous phosphatidylserine (PS) on platelet exocytosis and adhesion. PS, most commonly found in the phosphatidyl-l-serine (l-PS) form, is exposed on the outer leaflet of the cell membrane after the platelet is activated. Knowledge about the impact of exogenous phosphatidylserine on cell-to-cell communication is limited (particularly concentration and stereochemistry effects). This study found that platelets incubated in l-PS or phosphatidyl-d-serine (d-PS) are enriched to the same extent with their respective incubated PS. All levels of l-PS enrichment also showed an increase in platelet cholesterol, but only the 50μM d-PS incubation showed an increase in cholesterol. The uptake of d-PS induced the secretion of granules and manufactured platelet activating factor (PAF) in otherwise unstimulated platelets. The uptake of l-PS had a greater impact on platelet stimulation by decreasing both the amount of δ-granule secretion and the amount of PAF that was manufactured.
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39
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Fuentes E, Yameen B, Bong SJ, Salvador-Morales C, Palomo I, Vilos C. Antiplatelet effect of differentially charged PEGylated lipid-polymer nanoparticles. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2017; 13:1089-1094. [DOI: 10.1016/j.nano.2016.10.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 09/30/2016] [Accepted: 10/15/2016] [Indexed: 10/20/2022]
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40
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Abstract
Interest in the biology of mammalian septin proteins has undergone a birth in recent years. Originally identified as critical for yeast budding throughout the 1970s, the septin family is now recognized to extend from yeast to humans and is associated with a variety of events ranging from cytokinesis to vesicle trafficking. An emerging theme for septins is their presence at sites where active membrane or cytoplasmic partitioning is occurring. Here, we briefly review the mammalian septin protein family and focus on a prototypic human and mouse septin, termed SEPT5, that is expressed in the brain, heart, and megakaryocytes. Work from neurobiology laboratories has linked SEPT5 to the exocytic complex of neurons, with implications that SEPT5 regulates neurotransmitter release. Striking similarities exist between neurotransmitter release and the platelet-release reaction, which is a critical step in platelet response to vascular injury. Work from our laboratory has characterized the platelet phenotype from mice containing a targeted deletion of SEPT5. Most strikingly, platelets from SEPT5null animals aggregate and release granular contents in response to subthreshold levels of agonists. Thus, the characterization of a SEPT5-deficient mouse has linked SEPT5 to the Platelet exocytic process and, as such, illustrates it as an important protein for regulating platelet function. Recent data suggest that platelets contain a wide repertoire of different septin proteins and assemble to form macromolecular septin complexes. The mouse platelet provides an experimental framework to define septin function in hemostasis, with implications for neurobiology and beyond.
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Affiliation(s)
- Constantino Martinez
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
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41
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Donovan AJ, Kalkowski J, Szymusiak M, Wang C, Smith SA, Klie RF, Morrissey JH, Liu Y. Artificial Dense Granules: A Procoagulant Liposomal Formulation Modeled after Platelet Polyphosphate Storage Pools. Biomacromolecules 2016; 17:2572-81. [PMID: 27405511 PMCID: PMC8767982 DOI: 10.1021/acs.biomac.6b00577] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Granular platelet-sized polyphosphate nanoparticles (polyP NPs) were encapsulated in sterically stabilized liposomes, forming a potential, targeted procoagulant nanotherapy resembling human platelet dense granules in both structure and functionality. Dynamic light scattering (DLS) measurements reveal that artificial dense granules (ADGs) are colloidally stable and that the granular polyP NPs are encapsulated at high efficiencies. High-resolution scanning transmission electron microscopy (HR-STEM) indicates that the ADGs are monodisperse particles with a 150 nm diameter dense core consisting of P, Ca, and O surrounded by a corrugated 25 nm thick shell containing P, C, and O. Further, the ADGs manifest promising procoagulant activity: Detergent solubilization by Tween 20 or digestion of the lipid envelope by phospholipase C (PLC) allows for ADGs to trigger autoactivation of Factor XII (FXII), the first proteolytic step in the activation of the contact pathway of clotting. Moreover, ADGs' ability to reduce the clotting time of human plasma in the presence of PLC further demonstrate the feasibility to develop ADGs into a potential procoagulant nanomedicine.
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Affiliation(s)
- Alexander J. Donovan
- Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Joseph Kalkowski
- Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Magdalena Szymusiak
- Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Canhui Wang
- Department of Physics, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Stephanie A. Smith
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Robert F. Klie
- Department of Physics, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - James H. Morrissey
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
| | - Ying Liu
- Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL 60607, United States
- Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607, United States
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42
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Lu Y, Li Q, Liu YY, Sun K, Fan JY, Wang CS, Han JY. Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases. Sci Rep 2015; 5:13824. [PMID: 26345207 PMCID: PMC4561902 DOI: 10.1038/srep13824] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 08/06/2015] [Indexed: 11/15/2022] Open
Abstract
Caffeic acid (CA), one of the active constituents of Radix Salvia miltiorrhizae, exhibits antioxidant and anti-inflammatory activities. However, few studies have assessed the ability of CA to inhibit platelet mediated thrombus generation in vivo. In this study, we investigated the antithrombotic effect of CA in mouse cerebral arterioles and venules using intravital microscopy. The antiplatelet activity of CA in ADP stimulated mouse platelets in vitro was also examined in attempt to explore the underlying mechanism. Our results demonstrated that CA (1.25–5 mg/kg) significantly inhibited thrombus formation in vivo. In vitro, CA (25–100 μM) inhibited ADP-induced platelet aggregation, P-selectin expression, ATP release, Ca2+ mobilization, and integrin αIIbβ3 activation. Additionally, CA attenuated p38, ERK, and JNK activation, and enhanced cAMP levels. Taken together, these data provide evidence for the inhibition of CA on platelet-mediated thrombosis in vivo, which is, at least partly, mediated by interference in phosphorylation of ERK, p38, and JNK leading to elevation of cAMP and down-regulation of P-selectin expression and αIIbβ3 activation. These results suggest that CA may have potential for the treatment of aberrant platelet activation-related diseases.
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Affiliation(s)
- Yu Lu
- Department of gynaecology, Beijing Royal Integrative Medicine Hospital, Beijing, China.,Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.,Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
| | - Quan Li
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China
| | - Yu-Ying Liu
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China
| | - Kai Sun
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China
| | - Jing-Yu Fan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
| | - Chuan-She Wang
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.,Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China
| | - Jing-Yan Han
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.,Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.,Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China
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43
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Walker B, Schmid E, Russo A, Schmidt EM, Burk O, Münzer P, Velic A, Macek B, Schaller M, Schwab M, Seabra MC, Gawaz M, Lang F, Borst O. Impact of the serum- and glucocorticoid-inducible kinase 1 on platelet dense granule biogenesis and secretion. J Thromb Haemost 2015; 13:1325-34. [PMID: 25944668 DOI: 10.1111/jth.12998] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Platelet secretion is critical to development of acute thrombotic occlusion. Platelet dense granules contain a variety of important hemostatically active substances. Nevertheless, biogenesis of platelet granules is poorly understood. OBJECTIVES Serum- and glucocorticoid-inducible kinase 1 (SGK1) has been shown to be highly expressed in platelets and megakaryocytes, but its role in the regulation of platelet granule biogenesis and its impact on thrombosis has not been investigated so far. METHODS AND RESULTS Electron microscopy analysis of the platelet ultrastructure revealed a significant reduction in the number and packing of dense granules in platelets lacking SGK1 (sgk1(-/-) ). In sgk1(-/-) platelets serotonin content was significantly reduced and activation-dependent secretion of ATP, serotonin and CD63 significantly impaired. In vivo adhesion after carotis ligation was significantly decreased in platelets lacking SGK1 and occlusive thrombus formation after FeCl3 -induced vascular injury was significantly diminished in sgk1(-/-) mice. Transcript levels and protein abundance of dense granule biogenesis regulating GTPase Rab27b were significantly reduced in sgk1(-/-) platelets without affecting Rab27b mRNA stability. In MEG-01 cells transfection with constitutively active (S422) (D) SGK1 but not with inactive (K127) (N) SGK1 significantly enhanced Rab27b mRNA levels. Sgk1(-/-) megakaryocytes show significantly reduced expression of Rab27b and serotonin/CD63 levels compared with sgk1(+/+) megakaryocytes. Proteome analysis identified nine further vesicular transport proteins regulated by SGK1, which may have an impact on impaired platelet granule biogenesis in sgk1(-/-) platelets independent of Rab27b. CONCLUSIONS The present observations identify SGK1 as a novel powerful regulator of platelet dense granule biogenesis, platelet secretion and thrombus formation. SGK1 is at least partially effective because it regulates transcription of Rab27b in megakaryocytes.
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Affiliation(s)
- B Walker
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - E Schmid
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen, Germany
| | - A Russo
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - E-M Schmidt
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - O Burk
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
| | - P Münzer
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - A Velic
- Proteom Center Tübingen, University of Tübingen, Tübingen, Germany
| | - B Macek
- Proteom Center Tübingen, University of Tübingen, Tübingen, Germany
| | - M Schaller
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - M Schwab
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- Department of Clinical Pharmacology, University Hospital, Tübingen, Germany
| | - M C Seabra
- Molecular Medicine, National Heart and Lung Institute, Imperial College London, London, UK
| | - M Gawaz
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany
| | - F Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - O Borst
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany
- Department of Physiology, University of Tübingen, Tübingen, Germany
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44
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Koseoglu S, Meyer A, Kim D, Meyer BM, Wang Y, Dalluge JJ, Haynes CL. Analytical characterization of the role of phospholipids in platelet adhesion and secretion. Anal Chem 2015; 87:413-21. [PMID: 25439269 PMCID: PMC4287828 DOI: 10.1021/ac502293p] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 12/02/2014] [Indexed: 12/19/2022]
Abstract
The cellular phospholipid membrane plays an important role in cell function and cell-cell communication, but its biocomplexity and dynamic nature presents a challenge for examining cellular uptake of phospholipids and the resultant effects on cell function. Platelets, small anuclear circulating cell bodies that influence a wide variety of physiological functions through their dynamic secretory and adhesion behavior, present an ideal platform for exploring the effects of exogenous phospholipids on membrane phospholipid content and cell function. In this work, a broad range of platelet functions are quantitatively assessed by leveraging a variety of analytical chemistry techniques, including ultraperformance liquid chromatography-tandem electrospray ionization mass spectrometry (UPLC-MS/MS), vasculature-mimicking microfluidic analysis, and single cell carbon-fiber microelectrode amperometry (CFMA). The relative enrichments of phosphatidylserine (PS) and phosphatidylethanolamine (PE) were characterized with UPLC-MS/MS, and the effects of the enrichment of these two phospholipids on both platelet secretory behavior and adhesion were examined. Results show that, in fact, both PS and PE influence platelet adhesion and secretion. PS was enriched dramatically and decreased platelet adhesion as well as secretion from δ-, α-, and lysosomal granules. PE enrichment was moderate and increased secretion from platelet lysosomes. These insights illuminate the critical connection between membrane phospholipid character and platelet behavior, and both the methods and results presented herein are likely translatable to other mammalian cell systems.
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Affiliation(s)
- Secil Koseoglu
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
| | - Audrey
F. Meyer
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
| | - Donghyuk Kim
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
| | - Ben M. Meyer
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
| | - Yiwen Wang
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
| | - Joseph J. Dalluge
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
| | - Christy L. Haynes
- University of Minnesota, Department of
Chemistry, 207 Pleasant
Street SE, Minneapolis, Minnesota 55455, United States
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45
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Aoui C, Prigent A, Sut C, Tariket S, Hamzeh-Cognasse H, Pozzetto B, Richard Y, Cognasse F, Laradi S, Garraud O. The signaling role of CD40 ligand in platelet biology and in platelet component transfusion. Int J Mol Sci 2014; 15:22342-22364. [PMID: 25479079 PMCID: PMC4284712 DOI: 10.3390/ijms151222342] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 11/25/2014] [Accepted: 11/27/2014] [Indexed: 12/13/2022] Open
Abstract
The CD40 ligand (CD40L) is a transmembrane molecule of crucial interest in cell signaling in innate and adaptive immunity. It is expressed by a variety of cells, but mainly by activated T-lymphocytes and platelets. CD40L may be cleaved into a soluble form (sCD40L) that has a cytokine-like activity. Both forms bind to several receptors, including CD40. This interaction is necessary for the antigen specific immune response. Furthermore, CD40L and sCD40L are involved in inflammation and a panoply of immune related and vascular pathologies. Soluble CD40L is primarily produced by platelets after activation, degranulation and cleavage, which may present a problem for transfusion. Soluble CD40L is involved in adverse transfusion events including transfusion related acute lung injury (TRALI). Although platelet storage designed for transfusion occurs in sterile conditions, platelets are activated and release sCD40L without known agonists. Recently, proteomic studies identified signaling pathways activated in platelet concentrates. Soluble CD40L is a good candidate for platelet activation in an auto-amplification loop. In this review, we describe the immunomodulatory role of CD40L in physiological and pathological conditions. We will focus on the main signaling pathways activated by CD40L after binding to its different receptors.
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Affiliation(s)
- Chaker Aoui
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
- French Blood Establishment, EFS Auvergne-Loire, Saint-Etienne 42023, France
| | - Antoine Prigent
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
- French Blood Establishment, EFS Auvergne-Loire, Saint-Etienne 42023, France
| | - Caroline Sut
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
| | - Sofiane Tariket
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
| | - Hind Hamzeh-Cognasse
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
| | - Bruno Pozzetto
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
| | - Yolande Richard
- INSERMu1016, Institut Cochin, Departement “Infection, Immunity and Inflammation”, Paris 75014, France; E-Mail:
- CNRS-UMR8104, Cochin Institute, Paris 75014, France
- Université Paris-Descartes, Sorbonne Paris Cité, Paris 75270, France
| | - Fabrice Cognasse
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
- French Blood Establishment, EFS Auvergne-Loire, Saint-Etienne 42023, France
| | - Sandrine Laradi
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
- French Blood Establishment, EFS Auvergne-Loire, Saint-Etienne 42023, France
| | - Olivier Garraud
- Immunity of Mucosa and Pathogen Agents Group (GIMAP-EA3064), University of Lyon, Saint-Etienne 42023, France; E-Mails: (A.P.); (C.S.); (S.T.); (H.H-C.); (B.P.); (S.L.); (O.G.)
- Institut National de Transfusion Sanguine (INTS), Paris 75739, France
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Geraldo RB, Sathler PC, Lourenço AL, Saito MS, Cabral LM, Rampelotto PH, Castro HC. Platelets: still a therapeutical target for haemostatic disorders. Int J Mol Sci 2014; 15:17901-19. [PMID: 25295482 PMCID: PMC4227196 DOI: 10.3390/ijms151017901] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 08/26/2014] [Accepted: 09/23/2014] [Indexed: 11/16/2022] Open
Abstract
Platelets are cytoplasmatic fragments from bone marrow megakaryocytes present in blood. In this work, we review the basis of platelet mechanisms, their participation in syndromes and in arterial thrombosis, and their potential as a target for designing new antithrombotic agents. The option of new biotechnological sources is also explored.
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Affiliation(s)
- Reinaldo Barros Geraldo
- Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense (UFF), Niterói CEP 24210-130, RJ, Brazil.
| | - Plínio Cunha Sathler
- Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24030-215, RJ, Brazil.
| | - André Luiz Lourenço
- Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24030-215, RJ, Brazil.
| | - Max Seidy Saito
- Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24030-215, RJ, Brazil.
| | - Lucio M Cabral
- LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-590, RJ, Brazil.
| | - Pabulo Henrique Rampelotto
- Interdisciplinary Center for Biotechnology Research, Federal University of Pampa, Antônio Trilha Avenue, P.O. Box 1847, São Gabriel/RS 97300-000, Brazil.
| | - Helena Carla Castro
- Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense (UFF), Niterói CEP 24210-130, RJ, Brazil.
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Yang F, Dong A, Ahamed J, Sunkara M, Smyth SS. Granule cargo release from bone marrow-derived cells sustains cardiac hypertrophy. Am J Physiol Heart Circ Physiol 2014; 307:H1529-38. [PMID: 25239803 DOI: 10.1152/ajpheart.00951.2013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Bone marrow-derived inflammatory cells, including platelets, may contribute to the progression of pressure overload-induced left ventricular hypertrophy (LVH). However, the underlying mechanisms for this are still unclear. One potential mechanism is through release of granule cargo. Unc13-d(Jinx) (Jinx) mice, which lack Munc13-4, a limiting factor in vesicular priming and fusion, have granule secretion defects in a variety of hematopoietic cells, including platelets. In the current study, we investigated the role of granule secretion in the development of LVH and cardiac remodeling using chimeric mice specifically lacking Munc13-4 in marrow-derived cells. Pressure overload was elicited by transverse aortic constriction (TAC). Chimeric mice were created by bone marrow transplantation. Echocardiography, histology staining, immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were used to study LVH progression and inflammatory responses. Wild-type (WT) mice that were transplanted with WT bone marrow (WT→WT) and WT mice that received Jinx bone marrow (Jinx→WT) developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at late times (5 wk), mice lacking Munc13-4 in bone marrow-derived cells (Jinx→WT) failed to sustain the cardiac hypertrophy observed in WT chimeric mice. No difference in cardiac fibrosis was observed at early or late time points. Reinjection of WT platelets or platelet releasate partially restored cardiac hypertrophy in Jinx chimeric mice. These results suggest that sustained LVH in the setting of pressure overload depends on one or more factors secreted from bone marrow-derived cells, possibly from platelets. Inhibiting granule cargo release may represent a novel target for preventing sustained LVH.
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Affiliation(s)
- Fanmuyi Yang
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky
| | - Anping Dong
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky
| | - Jasimuddin Ahamed
- Laboratory of Blood and Vascular Biology, Rockefeller University, New York, New York; and
| | - Manjula Sunkara
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky
| | - Susan S Smyth
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky; Lexington Veterans Affairs Medical Center, Lexington, Kentucky
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Lillicrap D. Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets. J Clin Invest 2014; 124:4231-3. [PMID: 25244090 DOI: 10.1172/jci77511] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Details of the pathophysiologic mechanisms that underlie complex disorders, such as the thrombo-occlusive events associated with myocardial infarction, stroke, and venous thromboembolism, are challenging to address. Recent advances have been made through the application of genome-wide association studies (GWAS) to identify genetic loci associated with plasma levels of procoagulant proteins and risk of thrombotic disease. GWAS have consistently identified the gene encoding syntaxin-binding protein 5 (STXBP5) in this context. STXBP5 is expressed in both endothelium and platelets, and SNPs within the STXBP5 locus have been associated with plasma levels of vWF and increased venous thrombosis risk. In this issue of the JCI, two complementary reports from the laboratories of Charles Lowenstein and Sidney Whiteheart describe studies that highlight the complexity of the function of STXBP5 in control of storage granule development and exocytosis in platelets and endothelium. Together, these studies demonstrate that STXBP5 differentially regulates exocytosis in these two cell types. While STXBP5 facilitates granule release from platelets, it inhibits secretion from the Weibel-Palade bodies (WPBs) of endothelial cells.
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Collagen can selectively trigger a platelet secretory phenotype via glycoprotein VI. PLoS One 2014; 9:e104712. [PMID: 25116206 PMCID: PMC4130581 DOI: 10.1371/journal.pone.0104712] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 07/11/2014] [Indexed: 11/22/2022] Open
Abstract
Platelets are not only central actors of hemostasis and thrombosis but also of other processes including inflammation, angiogenesis, and tissue regeneration. Accumulating evidence indicates that these “non classical” functions of platelets do not necessarily rely on their well-known ability to form thrombi upon activation. This suggests the existence of non-thrombotic alternative states of platelets activation. We investigated this possibility through dose-response analysis of thrombin- and collagen-induced changes in platelet phenotype, with regards to morphological and functional markers of platelet activation including shape change, aggregation, P-selectin and phosphatidylserine surface expression, integrin activation, and release of soluble factors. We show that collagen at low dose (0.25 µg/mL) selectively triggers a platelet secretory phenotype characterized by the release of dense- and alpha granule-derived soluble factors without causing any of the other major platelet changes that usually accompany thrombus formation. Using a blocking antibody to glycoprotein VI (GPVI), we further show that this response is mediated by GPVI. Taken together, our results show that platelet activation goes beyond the mechanisms leading to platelet aggregation and also includes alternative platelet phenotypes that might contribute to their thrombus-independent functions.
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50
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Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 2014; 124:2173-83. [PMID: 25082876 DOI: 10.1182/blood-2014-05-573543] [Citation(s) in RCA: 506] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses.
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