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Badimon L, Padro T, Arderiu G, Vilahur G, Borrell-Pages M, Suades R. Extracellular vesicles in atherothrombosis: From biomarkers and precision medicine to therapeutic targets. Immunol Rev 2022; 312:6-19. [PMID: 35996799 DOI: 10.1111/imr.13127] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global mortality. Extracellular vesicles (EVs) are small phospholipid vesicles that convey molecular bioactive cargoes and play essential roles in intercellular communication and, hence, a multifaceted role in health and disease. The present review offers a glimpse into the current state and up-to-date concepts on EV field. It also covers their association with several cardiovascular risk factors and ischemic conditions, being subclinical atherosclerosis of utmost relevance for prevention. Interestingly, we show that EVs hold promise as prognostic and diagnostic as well as predictive markers of ASCVD in the precision medicine era. We then report on the role of EVs in atherothrombosis, disentangling the mechanisms involved in the initiation, progression, and complication of atherosclerosis and showing their direct effect in the context of arterial thrombosis. Finally, their potential use for therapeutic intervention is highlighted.
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Affiliation(s)
- Lina Badimon
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain.,Cardiovascular Research Chair, UAB, Barcelona, Spain
| | - Teresa Padro
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Gemma Arderiu
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Gemma Vilahur
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Borrell-Pages
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Rosa Suades
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
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2
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Dludla PV, Nkambule BB, Nyambuya TM, Ziqubu K, Mabhida SE, Mxinwa V, Mokgalaboni K, Ndevahoma F, Hanser S, Mazibuko-Mbeje SE, Basson AK, Sabbatinelli J, Tiano L. Vitamin C intake potentially lowers total cholesterol to improve endothelial function in diabetic patients at increased risk of cardiovascular disease: A systematic review of randomized controlled trials. Front Nutr 2022; 9:1011002. [PMID: 36386907 PMCID: PMC9659906 DOI: 10.3389/fnut.2022.1011002] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/29/2022] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Vitamin C is one of the most consumed dietary compounds and contains abundant antioxidant properties that could be essential in improving metabolic function. Thus, the current systematic review analyzed evidence on the beneficial effects of vitamin C intake on cardiovascular disease (CVD)-related outcomes in patients with diabetes or metabolic syndrome. METHODS To identify relevant randomized control trials (RCTs), a systematic search was run using prominent search engines like PubMed and Google Scholar, from beginning up to March 2022. The modified Black and Downs checklist was used to assess the quality of evidence. RESULTS Findings summarized in the current review favor the beneficial effects of vitamin C intake on improving basic metabolic parameters and lowering total cholesterol levels to reduce CVD-risk in subjects with type 2 diabetes or related metabolic diseases. Moreover, vitamin C intake could also reduce the predominant markers of inflammation and oxidative stress like C-reactive protein, interleukin-6, and malondialdehyde. Importantly, these positive outcomes were consistent with improved endothelial function or increased blood flow in these subjects. Predominantly effective doses were 1,000 mg/daily for 4 weeks up to 12 months. The included RCTs presented with the high quality of evidence. CONCLUSION Clinical evidence on the beneficial effects of vitamin C intake or its impact on improving prominent markers of inflammation and oxidative stress in patients with diabetes is still limited. Thus, more RCTs are required to solidify these findings, which is essential to better manage diabetic patients at increased risk of developing CVD.
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Affiliation(s)
- Phiwayinkosi V. Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Bongani B. Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Tawanda M. Nyambuya
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek, Namibia
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho, South Africa
| | - Sihle E. Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - Vuyolwethu Mxinwa
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Kabelo Mokgalaboni
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
- Department of Life and Consumer Sciences, University of South Africa, Florida Campus, Roodepoort, South Africa
| | - Fransina Ndevahoma
- Department of Health Sciences, Namibia University of Science and Technology, Windhoek, Namibia
| | - Sidney Hanser
- Department of Physiology and Environmental Health, University of Limpopo, Sovenga, South Africa
| | | | - Albertus K. Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
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3
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Bordin A, Chirivì M, Pagano F, Milan M, Iuliano M, Scaccia E, Fortunato O, Mangino G, Dhori X, De Marinis E, D'Amico A, Miglietta S, Picchio V, Rizzi R, Romeo G, Pulcinelli F, Chimenti I, Frati G, De Falco E. Human platelet lysate-derived extracellular vesicles enhance angiogenesis through miR-126. Cell Prolif 2022; 55:e13312. [PMID: 35946052 DOI: 10.1111/cpr.13312] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/08/2022] [Accepted: 06/23/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Extracellular vesicles (EVs) are key biological mediators of several physiological functions within the cell microenvironment. Platelets are the most abundant source of EVs in the blood. Similarly, platelet lysate (PL), the best platelet derivative and angiogenic performer for regenerative purposes, is enriched of EVs, but their role is still too poorly discovered to be suitably exploited. Here, we explored the contribution of the EVs in PL, by investigating the angiogenic features extrapolated from that possessed by PL. METHODS We tested angiogenic ability and molecular cargo in 3D bioprinted models and by RNA sequencing analysis of PL-derived EVs. RESULTS A subset of small vesicles is highly represented in PL. The EVs do not retain aggregation ability, preserving a low redox state in human umbilical vein endothelial cells (HUVECs) and increasing the angiogenic tubularly-like structures in 3D endothelial bioprinted constructs. EVs resembled the miRNome profile of PL, mainly enriched with small RNAs and a high amount of miR-126, the most abundant angiogenic miRNA in platelets. The transfer of miR-126 by EVs in HUVEC after the in vitro inhibition of the endogenous form, restored angiogenesis, without involving VEGF as a downstream target in this system. CONCLUSION PL is a biological source of available EVs with angiogenic effects involving a miRNAs-based cargo. These properties can be exploited for targeted molecular/biological manipulation of PL, by potentially developing a product exclusively manufactured of EVs.
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Affiliation(s)
- Antonella Bordin
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Maila Chirivì
- Department of Pathophysiology and Transplantation, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Pagano
- Institute of Biochemistry and Cell Biology, National Research Council of Italy (IBBC-CNR), Monterotondo, Rome, Italy
| | - Marika Milan
- UOC Neurologia, Fondazione Ca'Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Marco Iuliano
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Eleonora Scaccia
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Orazio Fortunato
- Tumor Genomics Unit, Department of Research, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy
| | - Giorgio Mangino
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Xhulio Dhori
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Elisabetta De Marinis
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Alessandra D'Amico
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Selenia Miglietta
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, La Sapienza University of Rome, Rome, Italy
| | - Vittorio Picchio
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Roberto Rizzi
- Istituto Nazionale Genetica Molecolare INGM 'Romeo ed Enrica Invernizzi', Milan, Italy
- Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Milan, Italy
| | - Giovanna Romeo
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Fabio Pulcinelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Isotta Chimenti
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Giacomo Frati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzili, Italy
| | - Elena De Falco
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
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Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis. Cells 2022; 11:cells11111845. [PMID: 35681540 PMCID: PMC9180657 DOI: 10.3390/cells11111845] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023] Open
Abstract
Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality all over the world. Extracellular vesicles (EVs), small lipid-bilayer membrane vesicles released by most cellular types, exert pivotal and multifaceted roles in physiology and disease. Emerging evidence emphasizes the importance of EVs in intercellular communication processes with key effects on cell survival, endothelial homeostasis, inflammation, neoangiogenesis, and thrombosis. This review focuses on EVs as effective signaling molecules able to both derail vascular homeostasis and induce vascular dysfunction, inflammation, plaque progression, and thrombus formation as well as drive anti-inflammation, vascular repair, and atheroprotection. We provide a comprehensive and updated summary of the role of EVs in the development or regression of atherosclerotic lesions, highlighting the link between thrombosis and inflammation. Importantly, we also critically describe their potential clinical use as disease biomarkers or therapeutic agents in atherothrombosis.
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Morel O, Marchandot B, Jesel L, Sattler L, Trimaille A, Curtiaud A, Ohana M, Fafi-Kremer S, Schini-Kerth V, Grunebaum L, Freyssinet JM. Microparticles in COVID-19 as a link between lung injury extension and thrombosis. ERJ Open Res 2021; 7:00954-2020. [PMID: 34159187 PMCID: PMC8209522 DOI: 10.1183/23120541.00954-2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/08/2021] [Indexed: 11/12/2022] Open
Abstract
Among the distinctive features of coronavirus disease 2019 (COVID-19), numerous reports have stressed the importance of vascular damage associated with coagulopathy onset [1]. Histological analysis of pulmonary vessels in patients with COVID-19 revealed severe endothelial injury associated with intracellular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and disrupted endothelial cell membranes together with widespread thrombosis and occlusion of alveolar capillaries. Microparticles (MPs) shed by apoptotic/stimulated cells of various cellular lineages, including platelets, leukocytes, macrophages or endothelial cells, are reliable markers of vascular damage [2] released upon pro-inflammatory conditions and behave as active participants in the early steps of clot formation [3]. Circulating MPs promote procoagulant responses due to the exposure of tissue factor, the physiological activator of the coagulation cascade, and of negatively charged phospholipids, such as phosphatidylserine, required for the assembly of the tenase and prothrombinase coagulation complexes ultimately leading to thrombin generation, through which they can precisely be quantified [4]. MPs carry angiotensin-converting enzyme (ACE)1 and upregulate ACE1 expression in neighbouring endothelial cells [5]. By contrast, exosomes were recently reported to convey ACE2, the cell-entry receptor for SARS-CoV-2 [4], in the vasculature [6]. ACE2 converts angiotensin II (Ang II) into angiotensin 1–7 (Ang 1–7), which by virtue of its actions on the Mas receptor, limits the noxious effects of Ang II. Pioneering data have demonstrated that the renin–angiotensin system has a crucial role in severe acute injury and that ACE2 has a protective role in acute lung injury mediated by SARS-CoV [7]. According to this paradigm, the loss of ACE2 function following binding by SARS-CoV-2 may contribute to unopposed Ang II accumulation that further exacerbates tissue injury and promotes inflammation, MPs release and thrombosis. During SARS-CoV-2 infection, we hypothesised that various factors including inflammatory burden, Ang II, altered shear stress and hypoxic vasoconstriction, could enhance MPs shedding by various cell lineages including the alveolar vascular endothelium and contribute to clot formation. Procoagulant microparticles are associated with the extent of lung injuries in #COVID19 and pulmonary thrombosishttps://bit.ly/3eX2LPc
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Affiliation(s)
- Olivier Morel
- Université de Strasbourg, Faculté de Médecine, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France.,UMR INSERM 1260, Regenerative Nanomedicine, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
| | - Benjamin Marchandot
- Université de Strasbourg, Faculté de Médecine, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Laurence Jesel
- Université de Strasbourg, Faculté de Médecine, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France.,UMR INSERM 1260, Regenerative Nanomedicine, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
| | - Laurent Sattler
- Université de Strasbourg, Pôle de Biologie, Département d'Hémostase, Centre Hospitalier Universitaire, Strasbourg, France
| | - Antonin Trimaille
- Université de Strasbourg, Faculté de Médecine, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Anais Curtiaud
- Université de Strasbourg, Faculté de Médecine, Pôle d'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Mickael Ohana
- Université de Strasbourg, Département de Radiologie, Centre Hospitalier Universitaire, Strasbourg, France
| | - Samira Fafi-Kremer
- Université de Strasbourg, Pôle de Biologie, Département de Virologie, Centre Hospitalier Universitaire, Strasbourg, France
| | - Valerie Schini-Kerth
- UMR INSERM 1260, Regenerative Nanomedicine, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
| | - Lelia Grunebaum
- Université de Strasbourg, Pôle de Biologie, Département d'Hémostase, Centre Hospitalier Universitaire, Strasbourg, France
| | - Jean-Marie Freyssinet
- Université de Strasbourg, Pôle de Biologie, Département d'Hémostase, Centre Hospitalier Universitaire, Strasbourg, France
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Osman A, Benameur T, Korashy HM, Zeidan A, Agouni A. Interplay between Endoplasmic Reticulum Stress and Large Extracellular Vesicles (Microparticles) in Endothelial Cell Dysfunction. Biomedicines 2020; 8:E409. [PMID: 33053883 PMCID: PMC7599704 DOI: 10.3390/biomedicines8100409] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 09/26/2020] [Accepted: 10/03/2020] [Indexed: 12/19/2022] Open
Abstract
Upon increased demand for protein synthesis, accumulation of misfolded and/or unfolded proteins within the endoplasmic reticulum (ER), a pro-survival response is activated termed unfolded protein response (UPR), aiming at restoring the proper function of the ER. Prolonged activation of the UPR leads, however, to ER stress, a cellular state that contributes to the pathogenesis of various chronic diseases including obesity and diabetes. ER stress response by itself can result in endothelial dysfunction, a hallmark of cardiovascular disease, through various cellular mechanisms including apoptosis, insulin resistance, inflammation and oxidative stress. Extracellular vesicles (EVs), particularly large EVs (lEVs) commonly referred to as microparticles (MPs), are membrane vesicles. They are considered as a fingerprint of their originating cells, carrying a variety of molecular components of their parent cells. lEVs are emerging as major contributors to endothelial cell dysfunction in various metabolic disease conditions. However, the mechanisms underpinning the role of lEVs in endothelial dysfunction are not fully elucidated. Recently, ER stress emerged as a bridging molecular link between lEVs and endothelial cell dysfunction. Therefore, in the current review, we summarized the roles of lEVs and ER stress in endothelial dysfunction and discussed the molecular crosstalk and relationship between ER stress and lEVs in endothelial dysfunction.
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Affiliation(s)
- Aisha Osman
- Department of Pharmaceutical Sciences, College of Pharmacy, QU health, Qatar University, Doha 2713, Qatar; (A.O.); (H.M.K.)
| | - Tarek Benameur
- Department of Biomedical Sciences, College of Medicine, King Faisal University, P.O. Box 400, Al Ahsa 31982, Saudi Arabia;
| | - Hesham M. Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU health, Qatar University, Doha 2713, Qatar; (A.O.); (H.M.K.)
| | - Asad Zeidan
- Department of Basic Medical Sciences, College of Medicine, QU health, Qatar University, Doha 2713, Qatar;
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU health, Qatar University, Doha 2713, Qatar; (A.O.); (H.M.K.)
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Khan SA, Bhattacharjee S, Ghani MOA, Walden R, Chen QM. Vitamin C for Cardiac Protection during Percutaneous Coronary Intervention: A Systematic Review of Randomized Controlled Trials. Nutrients 2020; 12:E2199. [PMID: 32718091 PMCID: PMC7468730 DOI: 10.3390/nu12082199] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/28/2022] Open
Abstract
Percutaneous coronary intervention (PCI) is the preferred treatment for acute coronary syndrome (ACS) secondary to atherosclerotic coronary artery disease. This nonsurgical procedure is also used for selective patients with stable angina. Although the procedure is essential for restoring blood flow, reperfusion can increase oxidative stress as a side effect. We address whether intravenous infusion of vitamin C (VC) prior to PCI provides a benefit for cardioprotection. A total of eight randomized controlled trials (RCT) reported in the literature were selected from 371 publications through systematic literature searches in six electronic databases. The data of VC effect on cardiac injury biomarkers and cardiac function were extracted from these trials adding up to a total of 1185 patients. VC administration reduced cardiac injury as measured by troponin and CK-MB elevations, along with increased antioxidant reservoir, reduced reactive oxygen species (ROS) and decreased inflammatory markers. Improvement of the left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume (TLVV) showed a trend but inconclusive association with VC. Intravenous infusion of VC before PCI may serve as an effective method for cardioprotection against reperfusion injury.
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Affiliation(s)
- Sher Ali Khan
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, 1295 N. Martin Ave, Tucson, AZ 85721, USA; (S.A.K.); (S.B.)
| | - Sandipan Bhattacharjee
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, 1295 N. Martin Ave, Tucson, AZ 85721, USA; (S.A.K.); (S.B.)
| | | | - Rachel Walden
- Annette and Irwin Eskind Family Biomedical Library, Jean & Alexander Heard Libraries, Vanderbilt University, Nashville, TN 37203, USA;
| | - Qin M. Chen
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, 1295 N. Martin Ave, Tucson, AZ 85721, USA; (S.A.K.); (S.B.)
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8
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El Haouari M. Platelet Oxidative Stress and its Relationship with Cardiovascular Diseases in Type 2 Diabetes Mellitus Patients. Curr Med Chem 2019; 26:4145-4165. [PMID: 28982316 DOI: 10.2174/0929867324666171005114456] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 06/07/2017] [Accepted: 06/07/2017] [Indexed: 01/01/2023]
Abstract
Enhanced platelet activation and thrombosis are linked to various cardiovascular diseases (CVD). Among other mechanisms, oxidative stress seems to play a pivotal role in platelet hyperactivity. Indeed, upon stimulation by physiological agonists, human platelets generate and release several types of reactive oxygen species (ROS) such as O2 -, H2O2 or OH-, further amplifying the platelet activation response via various signalling pathways, including, formation of isoprostanes, Ca2+ mobilization and NO inactivation. Furthermore, excessive platelet ROS generation, incorporation of free radicals from environment and/or depletion of antioxidants induce pro-oxidant, pro-inflammatory and platelet hyperaggregability effects, leading to the incidence of cardiovascular events. Here, we review the current knowledge regarding the effect of oxidative stress on platelet signaling pathways and its implication in CVD such as type 2 diabetes mellitus. We also summarize the role of natural antioxidants included in vegetables, fruits and medicinal herbs in reducing platelet function via an oxidative stress-mediated mechanism.
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Affiliation(s)
- Mohammed El Haouari
- Centre Regional des Metiers de l'Education et de la Formation de Taza (CRMEF - Taza), B.P: 1178 - Taza Gare, Morocco
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9
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Liu D, Pei D, Hu H, Gu G, Cui W. Effects and Mechanisms of Vitamin C Post-Conditioning on Platelet Activation after Hypoxia/Reoxygenation. Transfus Med Hemother 2019; 47:110-118. [PMID: 32355470 DOI: 10.1159/000500492] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Background Platelet activation occurs upon ischemia/reperfusion and is related to the generation of reactive oxygen species (ROS) during this process. Vitamin C (VC) is a powerful antioxidant. VC scavenges ROS, reduces platelet activation, and attenuates reperfusion injury. However, the effects of VC on platelets undergoing hypoxia/reoxygenation (H/R) remain unclear. Objectives Herein, we evaluated the effects of VC on platelets in vitro following H/R and the related mechanisms. Method Fresh platelets were collected from 67 volunteers at the Blood Center of Hebei Province. Platelets were diluted with saline to a concentration of 2.00 × 10<sup>11</sup>/L. Aggregation and the curve slope were evaluated within 4 h with a whole-blood impedance analyzer. To determine the optimal experimental time, platelets were treated with hypoxia or reoxygenation for different times, and impedance aggregometry was carried out by measuring changes in electrical impedance induced by arachidonic acid (0.5 mM) and adenosine diphosphate (10 µM), thereby establishing the H/R model. Three antioxidants (VC, melatonin, and probucol) were used to treat platelets after H/R, and impedance aggregometry was used to determine their effects on platelet aggregation. The influence of VC on apoptosis-related indicators was detected. ROS and the mitochondrial membrane potential were observed by inverted fluorescence microscopy and flow cytometry, respectively. Related protein levels were detected by Western blotting. Results ROS scavengers inhibited platelet activation and aggregation in a concentration-dependent manner. VC post-conditioning scavenged ROS, downregulated cytochrome C, Bax, and caspase-9 proteins, and upregulated Bcl-2 protein. These effects collectively blocked platelet apoptosis and inhibited platelet aggregation. Conclusions VC inhibited platelet aggregation by blocking apoptosis. Thus, VC may have applications in the treatment of platelet-related diseases.
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Affiliation(s)
- Demin Liu
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dongguo Pei
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Haijuan Hu
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guoqiang Gu
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Wei Cui
- Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, China
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11
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Abstract
Microparticles are a distinctive group of small vesicles, without nucleus, which are involved as significant modulators in several physiological and pathophysiological mechanisms. Plasma microparticles from various cellular lines have been subject of research. Data suggest that they are key players in development and manifestation of cardiovascular diseases and their presence, in high levels, is associated with chronic inflammation, endothelial damage and thrombosis. The strong correlation of microparticle levels with several outcomes in cardiovascular diseases has led to their utilization as biomarkers. Despite the limited clinical application at present, their significance emerges, mainly because their detection and enumeration methods are improving. This review article summarizes the evidence derived from research, related with the genesis and the function of microparticles in the presence of various cardiovascular risk factors and conditions. The current data provide a substrate for several theories of how microparticles influence various cellular mechanisms by transferring biological information.
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Affiliation(s)
- Christos Voukalis
- a Institute of Cardiovascular Sciences , University of Birmingham , Birmingham , UK
| | - Eduard Shantsila
- a Institute of Cardiovascular Sciences , University of Birmingham , Birmingham , UK
| | - Gregory Y H Lip
- b Liverpool Centre for Cardiovascular Science , University of Liverpool and Liverpool Heart & Chest Hospital , Liverpool , UK.,c Department of Clinical Medicine, Aalborg Thrombosis Research Unit , Aalborg University , Aalborg , Denmark
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12
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El-Gamal H, Parray AS, Mir FA, Shuaib A, Agouni A. Circulating microparticles as biomarkers of stroke: A focus on the value of endothelial- and platelet-derived microparticles. J Cell Physiol 2019; 234:16739-16754. [PMID: 30912147 DOI: 10.1002/jcp.28499] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/20/2019] [Accepted: 03/06/2019] [Indexed: 12/20/2022]
Abstract
Stroke is one of the leading causes of mortality and disability worldwide. Numerous pathophysiological mechanisms involving blood vessels, coagulation and inflammation contribute to the vascular occlusion. Perturbations in these pathways can be detected by numerous methods including changes in endoplasmic membrane remodeling and rearrangement leading to the shedding of microparticles (MPs) from various cellular origins in the blood. MPs are small membrane-derived vesicles that are shed from nearly all cells in the body in resting state or upon stimulation. MPs act as biological messengers to transfer information to adjacent and distant cells thus regulating various biological processes. MPs may be important biomarkers and tools for the identification of the risk and diagnosis of cerebrovascular diseases. Endothelial activation and dysfunction and altered thrombotic responses are two of the main features predisposing to stroke. Endothelial MPs (EMPs) have been recognized as both biomarkers and effectors of endothelial cell activation and injury while platelet-derived MPs (PMPs) carry a strong procoagulant potential and are activated in thrombotic states. Therefore, we reviewed here the role of EMPs and PMPs as biomarkers of stroke. Most studies reported high circulating levels of EMPs and PMPs in addition to other cell origins in stroke patients and have been linked to stroke severity, the size of infarction, and prognosis. The identification and quantification of EMPs and PMPs may thus be useful for the diagnosis and management of stroke.
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Affiliation(s)
- Heba El-Gamal
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Aijaz S Parray
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Fayaz A Mir
- Interim Translational Research Institute (iTRI), Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ashfaq Shuaib
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.,Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
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Santilli F, Marchisio M, Lanuti P, Boccatonda A, Miscia S, Davì G. Microparticles as new markers of cardiovascular risk in diabetes and beyond. Thromb Haemost 2018; 116:220-34. [DOI: 10.1160/th16-03-0176] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 04/19/2016] [Indexed: 12/25/2022]
Abstract
SummaryThe term microparticle (MP) identifies a heterogeneous population of vesicles playing a relevant role in the pathogenesis of vascular diseases, cancer and metabolic diseases such as diabetes mellitus. MPs are released by virtually all cell types by shedding during cell growth, proliferation, activation, apoptosis or senescence processes. MPs, in particular platelet- and endothelial-derived MPs (PMPs and EMPs), are increased in a wide range of thrombotic disorders, with an interesting relationship between their levels and disease pathophysiology, activity or progression. EMP plasma levels have been associated with several cardiovascular diseases and risk factors. PMPs are also shown to be involved in the progressive formation of atherosclerotic plaque and development of arterial thrombosis, especially in diabetic patients. Indeed, diabetes is characterised by an increased procoagulant state and by a hyperreactive platelet phenotype, with enhanced adhesion, aggregation, and activation. Elevated MP levels, such as TF+ MPs, have been shown to be one of the procoagulant determinants in patients with type 2 diabetes mellitus. Atherosclerotic plaque constitutes an opulent source of sequestered MPs, called “plaque” MPs. Otherwise, circulating MPs represent a TF reservoir, named “blood-borne” TF, challenging the dogma that TF is a constitutive protein expressed in minute amounts. “Blood-borne” TF is mainly harboured by PMPs, and it can be trapped within the developing thrombus. MP detection and enumeration by polychromatic flow cytometry (PFC) have opened interesting perspectives in clinical settings, particularly for the evaluation of MP numbers and phenotypes as independent marker of cardiovascular risk, disease and outcome in diabetic patients.
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Pernomian L, Moreira JD, Gomes MS. In the View of Endothelial Microparticles: Novel Perspectives for Diagnostic and Pharmacological Management of Cardiovascular Risk during Diabetes Distress. J Diabetes Res 2018; 2018:9685205. [PMID: 29862304 PMCID: PMC5971276 DOI: 10.1155/2018/9685205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 03/27/2018] [Accepted: 04/26/2018] [Indexed: 12/16/2022] Open
Abstract
Acute or chronic exposure to diabetes-related stressors triggers a specific psychological and behavior stress syndrome called diabetes distress, which underlies depressive symptoms in most diabetic patients. Distressed and/or depressive diabetic adults exhibit higher rates of cardiovascular mortality and morbidity, which have been correlated to macrovascular complications evoked by diabetic behavior stress. Recent experimental findings clearly point out that oxidative stress accounts for the vascular dysfunction initiated by the exposure to life stressors in diabetic conditions. Moreover, oxidative stress has been described as the main autocrine and paracrine mechanism of cardiovascular damage induced by endothelial microparticles (anuclear ectosomal microvesicles released from injured endothelial cells) in diabetic subjects. Such robust relationship between oxidative stress and cardiovascular diseases strongly suggests a critical role for endothelial microparticles as the primer messengers of the redox-dependent vascular dysfunction underlying diabetes distress. Here, we provide novel perspectives opened in the view of endothelial microparticles as promising diagnostic and pharmacotherapeutic biomarkers of cardiovascular risk in distressed diabetic patients.
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Affiliation(s)
- Larissa Pernomian
- Department of Biosciences Applied to Pharmacy, Faculty of Pharmaceutical Sciences from Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Jôsimar Dornelas Moreira
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mayara Santos Gomes
- Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences from Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
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Badimon L, Suades R, Arderiu G, Peña E, Chiva-Blanch G, Padró T. Microvesicles in Atherosclerosis and Angiogenesis: From Bench to Bedside and Reverse. Front Cardiovasc Med 2017; 4:77. [PMID: 29326946 PMCID: PMC5741657 DOI: 10.3389/fcvm.2017.00077] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 11/22/2017] [Indexed: 12/28/2022] Open
Abstract
Atherosclerosis (AT) is a progressive chronic disease involving lipid accumulation, fibrosis, and inflammation in medium and large-sized arteries, and it is the main cause of cardiovascular disease (CVD). AT is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Despite lipid-lowering drugs have shown to decrease the risk of cardiovascular events (CVEs), there is a significant burden of AT-related morbidity and mortality. Identification of subjects at increased risk for CVE as well as discovery of novel therapeutic targets for improved treatment strategies are still unmet clinical needs in CVD. Microvesicles (MVs), small extracellular plasma membrane particles shed by activated and apoptotic cells have been widely linked to the development of CVD. MVs from vascular and resident cells by facilitating exchange of biological information between neighboring cells serve as cellular effectors in the bloodstream and play a key role in all stages of disease progression. This article reviews the current knowledge on the role of MVs in AT and CVD. Attention is focused on novel aspects of MV-mediated regulatory mechanisms from endothelial dysfunction, vascular wall inflammation, oxidative stress, and apoptosis to coagulation and thrombosis in the progression and development of atherothrombosis. MV contribution to vascular remodeling is also discussed, with a particular emphasis on the effect of MVs on the crosstalk between endothelial cells and smooth muscle cells, and their role regulating the active process of AT-driven angiogenesis and neovascularization. This review also highlights the latest findings and main challenges on the potential prognostic, diagnostic, and therapeutic value of cell-derived MVs in CVD. In summary, MVs have emerged as new regulators of biological functions in atherothrombosis and might be instrumental in cardiovascular precision medicine; however, significant efforts are still needed to translate into clinics the latest findings on MV regulation and function.
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Affiliation(s)
- Lina Badimon
- Cardiovascular Research Center (ICCC) and CiberCV, Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain
- Cardiovascular Research Chair, UAB, Barcelona, Spain
| | - Rosa Suades
- Cardiovascular Research Center (ICCC) and CiberCV, Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain
| | - Gemma Arderiu
- Cardiovascular Research Center (ICCC) and CiberCV, Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain
| | - Esther Peña
- Cardiovascular Research Center (ICCC) and CiberCV, Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain
| | - Gemma Chiva-Blanch
- Cardiovascular Research Center (ICCC) and CiberCV, Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain
| | - Teresa Padró
- Cardiovascular Research Center (ICCC) and CiberCV, Sant Pau Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain
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Koganti S, Eleftheriou D, Brogan PA, Kotecha T, Hong Y, Rakhit RD. Microparticles and their role in coronary artery disease. Int J Cardiol 2017; 230:339-345. [DOI: 10.1016/j.ijcard.2016.12.108] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 12/04/2016] [Accepted: 12/17/2016] [Indexed: 12/16/2022]
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Li KY, Zheng L, Wang Q, Hu YW. Characteristics of erythrocyte-derived microvesicles and its relation with atherosclerosis. Atherosclerosis 2016; 255:140-144. [PMID: 27871771 DOI: 10.1016/j.atherosclerosis.2016.10.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 10/21/2016] [Accepted: 10/21/2016] [Indexed: 01/21/2023]
Abstract
Microvesicles are formed under many circumstances, especially in atheromatous plaques. Erythrocyte-derived microvesicles (ErMVs) have been proved to promote atherosclerosis by promoting hypercoagulation, mediating inflammation and inducing cell adhesion. Several clinical studies have reported potential roles of ErMVs in cardiovascular disease diagnosis, but the current understanding of ErMVs remains insufficient. In this paper, we will review current research on the formation and degradation of ErMVs and the possible effects of ErMVs in atherosclerosis, discuss potential clinical applications in cardiovascular disease, and hope to raise awareness of the relation with atherosclerosis.
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Affiliation(s)
- Kai-Yin Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China
| | - Lei Zheng
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qian Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan-Wei Hu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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Endothelial Microparticles Act as Novel Diagnostic and Therapeutic Biomarkers of Diabetes and Its Complications: A Literature Review. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9802026. [PMID: 27803933 PMCID: PMC5075589 DOI: 10.1155/2016/9802026] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 08/28/2016] [Accepted: 09/19/2016] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus- (DM-) related vascular diseases attract increased attention due to their high morbidity and mortality. The incidence of obesity, atherosclerosis, coronary heart disease, hypertension, and dyslipidemia is significantly higher in DM patients, with an earlier onset and faster progression compared with non-DM patients. DM-related vascular diseases including macrovascular and microvascular complications are characterized by endothelial dysfunction. Therefore, a better understanding of the etiology and mechanisms of endothelial dysfunction is important for the diagnosis and treatment of DM. Endothelial microparticles (EMPs) are new diagnostic and therapeutic targets and biomarkers in DM-related vascular disease. Circulating EMPs containing biologically active substances act as intercellular signals under physiological and pathological conditions. They serve as biological markers of altered vascular endothelium and reflect the pathological progression and diminished endothelial function of blood vessels. Recent evidence suggests that the plasma level of EMPs is significantly higher in DM patients than in healthy population and is significantly correlated with DM-related complications. These observations have prompted speculation that EMPs play a crucial role in the pathophysiology of DM. This review summarizes the known and potential roles of EMPs in the diagnosis, staging, treatment, and clinical prognosis of DM and related vascular diseases.
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Badimon L, Suades R, Fuentes E, Palomo I, Padró T. Role of Platelet-Derived Microvesicles As Crosstalk Mediators in Atherothrombosis and Future Pharmacology Targets: A Link between Inflammation, Atherosclerosis, and Thrombosis. Front Pharmacol 2016; 7:293. [PMID: 27630570 PMCID: PMC5005978 DOI: 10.3389/fphar.2016.00293] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 08/22/2016] [Indexed: 12/24/2022] Open
Abstract
Reports in the last decade have suggested that the role of platelets in atherosclerosis and its thrombotic complications may be mediated, in part, by local secretion of platelet-derived microvesicles (pMVs), small cell blebs released during the platelet activation process. MVs are the most abundant cell-derived microvesicle subtype in the circulation. High concentrations of circulating MVs have been reported in patients with atherosclerosis, acute vascular syndromes, and/or diabetes mellitus, suggesting a potential correlation between the quantity of microvesicles and the clinical severity of the atherosclerotic disease. pMVs are considered to be biomarkers of disease but new information indicates that pMVs are also involved in signaling functions. pMVs evoke or promote haemostatic and inflammatory responses, neovascularization, cell survival, and apoptosis, processes involved in the pathophysiology of cardiovascular disease. This review is focused on the complex cross-talk between platelet-derived microvesicles, inflammatory cells and vascular elements and their relevance in the development of the atherosclerotic disease and its clinical outcomes, providing an updated state-of-the art of pMV involvement in atherothrombosis and pMV potential use as therapeutic agent influencing cardiovascular biomedicine in the future.
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Affiliation(s)
- Lina Badimon
- Cardiovascular Research Center, Consejo Superior de Investigaciones Científicas - Institut Català de Ciències Cardiovasculars, Institut d'Investigació Biomèdica Sant Pau, Hospital Santa Creu i Sant PauBarcelona, Spain; Cardiovascular Research Chair, Universitat Autònoma de BarcelonaBarcelona, Spain
| | - Rosa Suades
- Cardiovascular Research Center, Consejo Superior de Investigaciones Científicas - Institut Català de Ciències Cardiovasculars, Institut d'Investigació Biomèdica Sant Pau, Hospital Santa Creu i Sant Pau Barcelona, Spain
| | - Eduardo Fuentes
- Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging, Universidad de TalcaTalca, Chile; Centro de Estudios en Alimentos Procesados, Conicyt-RegionalGore-Maule, Talca, Chile
| | - Iván Palomo
- Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging, Universidad de TalcaTalca, Chile; Centro de Estudios en Alimentos Procesados, Conicyt-RegionalGore-Maule, Talca, Chile
| | - Teresa Padró
- Cardiovascular Research Center, Consejo Superior de Investigaciones Científicas - Institut Català de Ciències Cardiovasculars, Institut d'Investigació Biomèdica Sant Pau, Hospital Santa Creu i Sant Pau Barcelona, Spain
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Amiral J, Seghatchian J. Measurement of extracellular vesicles as biomarkers of consequences or cause complications of pathological states, and prognosis of both evolution and therapeutic safety/efficacy. Transfus Apher Sci 2016; 55:23-34. [PMID: 27475803 DOI: 10.1016/j.transci.2016.07.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Utility of EVs, as biomarkers of cause or consequence of various pathological complications, and prognosis of blood components' therapy in terms of safety/efficacy and their potential associated hazards, primed by EVs involvements in pro-inflammatory, immunomodulatory and activations of both pro/anti-coagulatory and others associated pathways, as well as various cellular cross talks, are highlighted as the fundamental. Today EVs are becoming the "buzz" words of the current diagnosis, development and research [DDR] strategies, with the aim of ensuring safer therapeutic approaches in the current clinical practices, also incorporating their potential in long term cost effectiveness in health care systems. The main focus of this manuscript is to review the current opinions in some fundamental areas of EVs involvements in health and diseases. Firstly, our goal is highlighting what are EVs/MVs/MPs and how are they generated in physiology, pathology or blood products; classification and significance of EVs generated in vivo; followed by consequences and physiological/pathological induced effects of EVs generation in vivo. Secondly, specific cell origin EVs and association with malignancy; focus on EVs carrying TF and annexin V as a protective protein for harmful effects of EVs, and associations with LA; and incidence of anti-annexin V antibodies are also discussed. Thirdly, utility of EVs is presented: as diagnostic tools of disease markers; prognosis and follow-up of clinical states; evaluation of therapy efficacy; quality and risk assessment of blood products; followed by the laboratory tools for exploring, characterizing and measuring EVs, and/or their associated activity, using our own experiences of capture based assays. Finally, in perspective, the upcoming low volume sampling, fast, reliable and reproducibility and friendly use laboratory tools and the standardization of measurement methods are highlighted with the beneficial effects that we are witnessing in both wound healing and tissue remodeling, with an expected blockbuster status EVs as future therapeutic directions.
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Affiliation(s)
- Jean Amiral
- Hyphen BioMed, Neuville sur Oise, Paris, France.
| | - Jerard Seghatchian
- International Consultancy in Blood Components Quality/Safety Improvement, Audit/Inspection and DDR Strategies, London, UK
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21
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The diagnostic usefulness of capture assays for measuring global/specific extracellular micro-particles in plasma. Transfus Apher Sci 2015; 53:127-36. [PMID: 26572801 DOI: 10.1016/j.transci.2015.10.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Capture assays were developed and validated for measuring the global pro-coagulant activity of micro-particles (MPs, mainly originated from platelets), or specific extravascular cellular MPs (released from erythrocytes, leukocytes, monocytes, endothelial cells) as those exposing TF (MP-TF, mainly observed in patients with some cancers). Conversely to Flow Cytometry methods, these capture assays measure all coagulant activity associated with MPs, through thrombin generation (MP-Activity) or Factor Xa generation (MP-TF), and therefore they bring a complementary information, as they are more specific for the pro-coagulant activity associated with MPs. Small particles (<0.40 µ) exposing Phosphatidyl Serine (PS) exhibit a greater pro-coagulant surface than larger MPs (0.40 to >1.00 µ), those preferentially measured with flow cytometry. Activity associated with MPs is a consequence of disease but can also be a cause contributing to pathological processes and development of thrombo-embolic events. In many diseases, flow cytometry and capture assays do not totally correlate, and have different associations with disease evolution. Optimized capture based assays are presented and discussed, along with their performance characteristics and some applications. They can be performed in any technically skillful hemostasis laboratory, using a thermostated ELISA equipment, or an incubator. Dynamic ranges for MP-Activity assay is from <0.1 nM to >2.5 nM Phospholipids, expressed as Phosphatidyl Serine (PS) equivalent, in the tested dilution. For MP-TF the very sensitive bio-immunoassay reported allows measuring concentrations from <0.10 pg/ml (TF equivalent) to >5.00 pg/ml, in the assayed dilution. No measurable MP-TF was found in normals, although an important concentration was generated from whole blood treated with Lipo-Poly-Saccharides. Capture based assays are then highly useful in the laboratory setting for measuring the activities associated with pro-coagulant, or specific cellular MPs.
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22
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Extracellular vesicles as new pharmacological targets to treat atherosclerosis. Eur J Pharmacol 2015; 763:90-103. [PMID: 26142082 DOI: 10.1016/j.ejphar.2015.06.047] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/13/2015] [Accepted: 06/25/2015] [Indexed: 01/09/2023]
Abstract
Extracellular vesicles released by most cell types, include apoptotic bodies (ABs), microvesicles (MVs) and exosomes. They play a crucial role in physiology and pathology, contributing to "cell-to-cell" communication by modifying the phenotype and the function of target cells. Thus, extracellular vesicles participate in the key processes of atherosclerosis from endothelial dysfunction, vascular wall inflammation to vascular remodeling. The purpose of this review is to summarize recent findings on extracellular vesicle formation, structure, release and clearance. We focus on the deleterious and beneficial effects of extracellular vesicles in the development of atherosclerosis. The potential role of extracellular vesicles as biomarkers and pharmacological targets, their innate therapeutic capacity, or their use for novel drug delivery devices in atherosclerotic cardiovascular diseases will also be discussed.
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23
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Yang M, Bhopale VM, Thom SR. Ascorbic acid abrogates microparticle generation and vascular injuries associated with high-pressure exposure. J Appl Physiol (1985) 2015; 119:77-82. [PMID: 25977448 DOI: 10.1152/japplphysiol.00183.2015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 05/12/2015] [Indexed: 11/22/2022] Open
Abstract
We hypothesized that pathological changes associated with elevations in annexin V-positive microparticles (MPs) following high-pressure exposures can be abrogated by ascorbic acid in a murine model. Mice exposed for 2 h to 790-kPa air and killed at 2 or 13 h postdecompression exhibited over threefold elevations in circulating MPs, as well as subgroups bearing Ly6G, CD41, Ter119, CD31, and CD142 surface proteins. There was evidence of significant neutrophil activation, platelet-neutrophil interactions, and vascular injury to brain, omentum, psoas, and skeletal muscles assessed as leakage of high-molecular-weight dextran. Prophylactic ascorbic acid (500 mg/kg ip) administration prevented all postdecompression neutrophil changes and vascular injuries. Ascorbic acid administration immediately after decompression abrogated most changes, but evidence of vascular leakage in the brain and skeletal muscle at 13 h postdecompression persisted. No significant elevations in these parameters occurred after injection of ascorbic acid alone. The findings support the idea that MP production occurring with exposures to elevated gas pressure is an oxidative stress response and that antioxidants may offer protection from pathological effects associated with decompression.
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Affiliation(s)
- Ming Yang
- Department of Emergency Medicine, University of Maryland, Baltimore, Maryland
| | - Veena M Bhopale
- Department of Emergency Medicine, University of Maryland, Baltimore, Maryland
| | - Stephen R Thom
- Department of Emergency Medicine, University of Maryland, Baltimore, Maryland
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França CN, Izar MCDO, Amaral JBD, Tegani DM, Fonseca FAH. Microparticles as potential biomarkers of cardiovascular disease. Arq Bras Cardiol 2015; 104:169-74. [PMID: 25626759 PMCID: PMC4375661 DOI: 10.5935/abc.20140210] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 10/21/2014] [Indexed: 12/26/2022] Open
Abstract
Primary prevention of cardiovascular disease is a choice of great relevance because
of its impact on health. Some biomarkers, such as microparticles derived from
different cell populations, have been considered useful in the assessment of
cardiovascular disease. Microparticles are released by the membrane structures of
different cell types upon activation or apoptosis, and are present in the plasma of
healthy individuals (in levels considered physiological) and in patients with
different pathologies. Many studies have suggested an association between
microparticles and different pathological conditions, mainly the relationship with
the development of cardiovascular diseases. Moreover, the effects of different
lipid-lowering therapies have been described in regard to measurement of
microparticles. The studies are still controversial regarding the levels of
microparticles that can be considered pathological. In addition, the methodologies
used still vary, suggesting the need for standardization of the different protocols
applied, aiming at using microparticles as biomarkers in clinical practice.
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High dietary intake of vitamin C suppresses age-related thymic atrophy and contributes to the maintenance of immune cells in vitamin C-deficient senescence marker protein-30 knockout mice. Br J Nutr 2015; 113:603-9. [PMID: 25608928 DOI: 10.1017/s0007114514003857] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Vitamin C (VC) is an essential nutrient for humans and certain other animals. It has antioxidant properties and has been reported to ameliorate oxidative damage to lipids, DNA and proteins. However, the effects of VC on immune function are poorly understood, especially the influence of long-term high-dose VC intake on the number and function of immune cells. In the present study, to evaluate the immune effects of VC, VC-deficient senescence marker protein-30 knockout (SMP30KO) mice were fed a diet containing the recommended level of VC (20 mg/kg per d; 0·02 % VC) or a high level of VC (200 mg/kg per d; 0·2 % VC) for 1 year. The plasma VC concentration of the 0·02 % group was the same as that of age-matched C57BL/6 mice after 1 year of feeding; however, plasma VC concentration and thymus weight were significantly higher in the 0·2 % VC group than in the 0·02 % VC group. The total counts of leucocytes, lymphocytes, granulocytes and monocytes in the peripheral blood, as well as the number of splenocytes and thymocytes, were all significantly higher in the 0·2 % VC group than in the 0·02 % VC group. In addition, the number of naive T cells in peripheral blood lymphocytes, the number of memory T-cell populations in splenocytes, and the number of cluster of differentiation (CD)4⁺CD8⁺ or CD4⁺CD8⁻ or CD4⁻CD8⁺ T cells in thymocytes were all markedly higher in the 0·2 % VC group than in the 0·02 % VC group after 1 year of dietary treatment. These results suggest that a long-term high-dose intake of VC is effective in the maintenance of immune cells, partly through the suppression of age-related thymic involution in VC-deficient SMP30KO mice.
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Helbing T, Olivier C, Bode C, Moser M, Diehl P. Role of microparticles in endothelial dysfunction and arterial hypertension. World J Cardiol 2014; 6:1135-1139. [PMID: 25429325 PMCID: PMC4244610 DOI: 10.4330/wjc.v6.i11.1135] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 08/29/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Microparticles are small cell vesicles that can be released by almost all eukaryotic cells during cellular stress and cell activation. Within the last 1-2 decades it has been shown that microparticles are useful blood surrogate markers for different pathological conditions, such as vascular inflammation, coagulation and tumour diseases. Several studies have investigated the abundance of microparticles of different cellular origins in multiple cardiovascular diseases. It thereby has been shown that microparticles released by platelets, leukocytes and endothelial cells can be found in conditions of endothelial dysfunction, acute and chronic vascular inflammation and hypercoagulation. In addition to their function as surrogate markers, several studies indicate that circulating microparticles can fuse with distinct target cells, such as endothelial cells or leukocyte, and thereby deliver cellular components of their parental cells to the target cells. Hence, microparticles are a novel entity of circulating, paracrine, biological vectors which can influence the phenotype, the function and presumably even the transcriptome of their target cells.
This review article aims to give a brief overview about the microparticle biology with a focus on endothelial activation and arterial hypertension. More detailed information about the role of microparticles in pathophysiology and disease can be found in already published work.
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Wu SY, Mayneris-Perxachs J, Lovegrove JA, Todd S, Yaqoob P. Fish-oil supplementation alters numbers of circulating endothelial progenitor cells and microparticles independently of eNOS genotype. Am J Clin Nutr 2014; 100:1232-43. [PMID: 25332321 DOI: 10.3945/ajcn.114.088880] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Emerging cellular markers of endothelial damage and repair include endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs), respectively. Effects of long-chain (LC) n-3 (omega-3) polyunsaturated fatty acids (PUFAs) and the influence of genetic background on these markers are not known. OBJECTIVE We investigated effects of fish-oil supplementation on both classical and novel markers of endothelial function in subjects prospectively genotyped for the Asp298 endothelial nitric oxide synthase (eNOS) polymorphism and at moderate risk of cardiovascular disease (CVD). DESIGN A total of 84 subjects with moderate risk of CVD (GG: n = 40; GT/TT: n = 44) completed a randomized, double-blind, placebo-controlled, 8-wk crossover trial of fish-oil supplementation that provided 1.5 g LC n-3 PUFAs/d. Effects of genotype and fish-oil supplementation on the blood lipid profile, inflammatory markers, vascular function (by using peripheral artery tonometry), and numbers of circulating EPCs and EMPs (by using flow cytometry) were assessed. RESULTS There was no significant effect of fish-oil supplementation on blood pressure, plasma lipids, or plasma glucose, although there was a trend (P = 0.069) toward a decrease in the plasma triglyceride concentration after fish-oil supplementation compared with placebo treatment. GT/TT subjects tended to have higher concentrations of total cholesterol and low-density lipoprotein cholesterol, but vascular function was not affected by either treatment or eNOS genotype. Biochemical markers of endothelial function were also unaffected by treatment and eNOS genotype. In contrast, there was a significant effect of fish-oil supplementation on cellular markers of endothelial function. Fish-oil supplementation increased numbers of EPCs and reduced numbers of EMPs relative to those with placebo treatment, which potentially favored the maintenance of endothelial integrity. There was no influence of genotype for any cellular markers of endothelial function, which indicated that effects of fish-oil supplementation were independent of eNOS genotype. CONCLUSION Emerging cellular markers of endothelial damage, integrity, and repair appear to be sensitive to potentially beneficial modification by dietary n-3 PUFAs. This trial was registered at www.controlled-trials.com/isrctn as ISRCTN76272133.
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Affiliation(s)
- Szu-Yun Wu
- From the Hugh Sinclair Unit of Human Nutrition, Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (S-YW, JM-P, JAL, and PY) and the Department of Mathematics and Statistics (ST), University of Reading, Whiteknights, Reading, United Kingdom
| | - Jordi Mayneris-Perxachs
- From the Hugh Sinclair Unit of Human Nutrition, Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (S-YW, JM-P, JAL, and PY) and the Department of Mathematics and Statistics (ST), University of Reading, Whiteknights, Reading, United Kingdom
| | - Julie A Lovegrove
- From the Hugh Sinclair Unit of Human Nutrition, Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (S-YW, JM-P, JAL, and PY) and the Department of Mathematics and Statistics (ST), University of Reading, Whiteknights, Reading, United Kingdom
| | - Susan Todd
- From the Hugh Sinclair Unit of Human Nutrition, Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (S-YW, JM-P, JAL, and PY) and the Department of Mathematics and Statistics (ST), University of Reading, Whiteknights, Reading, United Kingdom
| | - Parveen Yaqoob
- From the Hugh Sinclair Unit of Human Nutrition, Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (S-YW, JM-P, JAL, and PY) and the Department of Mathematics and Statistics (ST), University of Reading, Whiteknights, Reading, United Kingdom
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Larson MC, Hillery CA, Hogg N. Circulating membrane-derived microvesicles in redox biology. Free Radic Biol Med 2014; 73:214-28. [PMID: 24751526 PMCID: PMC4465756 DOI: 10.1016/j.freeradbiomed.2014.04.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 04/09/2014] [Accepted: 04/11/2014] [Indexed: 01/20/2023]
Abstract
Microparticles or microvesicles (MVs) are subcellular membrane blebs shed from all cells in response to various stimuli. MVs carry a battery of signaling molecules, many of them related to redox-regulated processes. The role of MVs, either as a cause or as a result of cellular redox signaling, has been increasingly recognized over the past decade. This is in part due to advances in flow cytometry and its detection of MVs. Notably, recent studies have shown that circulating MVs from platelets and endothelial cells drive reactive species-dependent angiogenesis; circulating MVs in cancer alter the microenvironment and enhance invasion through horizontal transfer of mutated proteins and nucleic acids and harbor redox-regulated matrix metalloproteinases and procoagulative surface molecules; and circulating MVs from red blood cells and other cells modulate cell-cell interactions through scavenging or production of nitric oxide and other free radicals. Although our recognition of MVs in redox-related processes is growing, especially in the vascular biology field, much remains unknown regarding the various biologic and pathologic functions of MVs. Like reactive oxygen and nitrogen species, MVs were originally believed to have a solely pathological role in biology. And like our understanding of reactive species, it is now clear that MVs also play an important role in normal growth, development, and homeostasis. We are just beginning to understand how MVs are involved in various biological processes-developmental, homeostatic, and pathological-and the role of MVs in redox signaling is a rich and exciting area of investigation.
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Affiliation(s)
- Michael Craig Larson
- Department of Biophysics and Medical College of Wisconsin, Milwaukee, WI 53226, USA; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226, USA
| | - Cheryl A Hillery
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226, USA; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Neil Hogg
- Department of Biophysics and Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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29
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Microvesicles and diabetic complications--novel mediators, potential biomarkers and therapeutic targets. Acta Pharmacol Sin 2014; 35:433-43. [PMID: 24608676 DOI: 10.1038/aps.2013.188] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 12/12/2013] [Indexed: 12/13/2022]
Abstract
Microvesicles (MVs), also known as microparticles, are small membrane vesicles released from different cell types under different conditions. MVs have been detected in the circulation and in organs/tissues in various diseases, including diabetes. Patients with different types of diabetes and complications have different cellular MV patterns. Studies have shown that MVs may mediate vascular thrombosis, vascular inflammation, angiogenesis, and other pathological processes of the disease through their procoagulant, pro-inflammatory, pro-angiogenic, proteolytic, and other properties. Therefore, MVs contribute to the development of diabetic macrovascular and microvascular complications. In addition, clinical studies have indicated that changes in MV number and composition may reflect the pathophysiological conditions of disease, and therefore, may serve as potential biomarkers for diagnostic and prognostic use. Understanding MVs' involvement in the pathophysiological conditions may provide insight into disease mechanisms and would also be helpful for the development of novel therapeutic strategies in the future. Here, we review the latest publications from our group and other groups and focus on the involvement of MVs in diabetic complications.
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Lumsden NG, Andrews KL, Bobadilla M, Moore XL, Sampson AK, Shaw JA, Mizrahi J, Kaye DM, Dart AM, Chin-Dusting JPF. Endothelial dysfunction in patients with type 2 diabetes post acute coronary syndrome. Diab Vasc Dis Res 2013; 10:368-74. [PMID: 23673378 DOI: 10.1177/1479164113482593] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
UNLABELLED This single visit study examined whether endothelial function, in addition to cardiovascular (CV) risk factors and plasma microparticle content, was normalised in 15 patients with type 2 diabetes + acute coronary syndrome (ACS) (6 weeks-6 months post cardiac event) undergoing standard clinical care compared to 16 sex- and age-matched healthy controls. RESULTS While total and low-density lipoprotein (LDL) cholesterol levels were well controlled in the patients with type 2 diabetes + ACS, residual CV risk profiles such as increased body mass index (BMI), systolic blood pressure, glucose levels and triglycerides and lower high-density lipoprotein (HDL) levels were still apparent. Endothelium-dependent responses to acetylcholine (ACh) were significantly lower in type 2 diabetes + ACS patients compared to controls. Correspondingly, the reactive hyperaemic index (RHI) was lower in the patient cohort. Endothelial microparticle (EMP) levels (CD31(+), CD41(-)) were 40% lower in the patient cohort. Simultaneous analysis of platelet microparticle (PMP) levels (CD41(+)) showed no difference between cohorts. CONCLUSIONS Patients with type 2 diabetes suffering from recent ACS exhibit residual CV risk factors despite being on standard clinical care. In addition, these patients continue to present with endothelial dysfunction despite having lower levels of EMPs.
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Affiliation(s)
- Natalie G Lumsden
- Vascular Pharmacology and Heart Failure, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
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31
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Barteneva NS, Fasler-Kan E, Bernimoulin M, Stern JNH, Ponomarev ED, Duckett L, Vorobjev IA. Circulating microparticles: square the circle. BMC Cell Biol 2013; 14:23. [PMID: 23607880 PMCID: PMC3651414 DOI: 10.1186/1471-2121-14-23] [Citation(s) in RCA: 177] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 03/20/2013] [Indexed: 01/05/2023] Open
Abstract
Background The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes.
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Affiliation(s)
- Natasha S Barteneva
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, D-249, 200 Longwood Avenue, Boston, MA 02115, USA.
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32
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Baron M, Boulanger CM, Staels B, Tailleux A. Cell-derived microparticles in atherosclerosis: biomarkers and targets for pharmacological modulation? J Cell Mol Med 2012; 16:1365-76. [PMID: 22050954 PMCID: PMC3823207 DOI: 10.1111/j.1582-4934.2011.01486.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Cardiovascular diseases remain an important cause of morbi-mortality. Atherosclerosis, which predisposes to cardiovascular disorders such as myocardial infarction and stroke, develops silently over several decades. Identification of circulating biomarkers to evaluate cardiovascular event risk and pathology prognosis is of particular importance. Microparticles (MPs) are small vesicles released from cells upon apoptosis or activation. Microparticles are present in blood of healthy individuals. Studies showing a modification of their concentrations in patients with cardiovascular risk factors and after cardiovascular events identify MPs as potential biomarkers of disease. Moreover, the pathophysiological properties of MPs may contribute to atherosclerosis development. In addition, pharmacological compounds, used in the treatment of cardiovascular disease, can reduce plasma MP concentrations. Nevertheless, numerous issues remain to be solved before MP measurement can be applied as routine biological tests to improve cardiovascular risk prediction. In particular, prospective studies to identify the predictive values of MPs in pathologies such as cardiovascular diseases are needed to demonstrate whether MPs are useful biomarkers for the early detection of the disease and its progression.
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33
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Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P. Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction. Semin Dial 2011; 24:327-37. [PMID: 21682773 DOI: 10.1111/j.1525-139x.2011.00925.x] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro-inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.
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34
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Helal O, Defoort C, Robert S, Marin C, Lesavre N, Lopez-Miranda J, Risérus U, Basu S, Lovegrove J, McMonagle J, Roche HM, Dignat-George F, Lairon D. Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress. Nutr Metab Cardiovasc Dis 2011; 21:665-671. [PMID: 20399083 DOI: 10.1016/j.numecd.2010.01.004] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2009] [Revised: 12/18/2009] [Accepted: 01/05/2010] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS The Metabolic Syndrome (MetS) is associated with increased cardiovascular risk. Circulating microparticles (MP) are involved in the pathogenesis of atherothrombotic disorders and are raised in individual with CVD. We measured their level and cellular origin in subjects with MetS and analyzed their associations with 1/anthropometric and biological parameters of MetS, 2/inflammation and oxidative stress markers. METHODS AND RESULTS Eighty-eight subjects with the MetS according to the NCEP-ATPIII definition were enrolled in a bicentric study and compared to 27 healthy controls. AnnexinV-positive MP (TMP), MP derived from platelets (PMP), erythrocytes (ErMP), endothelial cells (EMP), leukocytes (LMP) and granulocytes (PNMP) were determined by flow cytometry. MetS subjects had significantly higher counts/μl of TMP (730.6±49.7 vs 352.8±35.6), PMP (416.0±43.8 vs 250.5±23.5), ErMP (243.8±22.1 vs 73.6±19.6) and EMP (7.8±0.8 vs 4.0±1.0) compared with controls. LMP and PNMP were not statistically different between groups. Multivariate analysis demonstrated that each criterion for the MetS influenced the number of TMP. Waist girth was a significant determinant of PMP and EMP level and blood pressure was correlated with EMP level. Glycemia positively correlated with PMP level whereas dyslipidemia influenced EMP and ErMP levels. Interestingly, the oxidative stress markers, plasma glutathione peroxydase and urinary 8-iso-prostaglandin F(2) α, independently influenced TMP and PMP levels whereas inflammatory markers did not, irrespective of MP type. CONCLUSION Increased levels of TMP, PMP, ErMP and EMP are associated with individual metabolic abnormalities of MetS and oxidative stress. Whether MP assessment may represent a marker for risk stratification or a target for pharmacological intervention deserves further investigation.
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Affiliation(s)
- O Helal
- UMR INSERM 476, INRA 1260, Univ Aix-Marseille, Faculté de Médecine, 27 Boulevard Jean Moulin, Marseille Cedex 05, France
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Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol 2011; 31:27-33. [PMID: 21160065 DOI: 10.1161/atvbaha.110.218123] [Citation(s) in RCA: 472] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. They play a remarkable role in coagulation, inflammation, endothelial function, and angiogenesis and thus disturb the vascular homeostasis, contributing to the progression of vascular diseases. As a cause or a consequence, elevated levels of EMP were found in plasma from patients with vascular diseases, where they serve as a surrogate marker of endothelial function. More recent data challenged the presumed deleterious role of EMP because they could promote cell survival, exert antiinflammatory effects, counteract coagulation processes, or induce endothelial regeneration. This review focuses on the ambivalent role of EMP in vascular homeostasis.
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Affiliation(s)
- Françoise Dignat-George
- INSERM UMR-970, Paris Cardiovascular Research Center, 56 rue Leblanc, 75373 Paris Cedex 15, France
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36
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Morel O, Kessler L, Ohlmann P, Bareiss P. Diabetes and the platelet: Toward new therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis 2010; 212:367-76. [DOI: 10.1016/j.atherosclerosis.2010.03.019] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2009] [Revised: 03/05/2010] [Accepted: 03/18/2010] [Indexed: 01/21/2023]
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Affiliation(s)
- Francesco Violi
- Divisione I Clinica Medica, Università Sapienza, Viale del Policlinico 155, Roma, 00161, Italy.
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38
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Madden LA, Laden G. Gas bubbles may not be the underlying cause of decompression illness – The at-depth endothelial dysfunction hypothesis. Med Hypotheses 2009; 72:389-92. [PMID: 19128890 DOI: 10.1016/j.mehy.2008.11.022] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 11/05/2008] [Accepted: 11/07/2008] [Indexed: 01/20/2023]
Affiliation(s)
- Leigh A Madden
- Postgraduate Medical Institute, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
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Leroyer AS, Tedgui A, Boulanger CM. Microparticles and type 2 diabetes. DIABETES & METABOLISM 2008; 34 Suppl 1:S27-32. [PMID: 18358424 DOI: 10.1016/s1262-3636(08)70100-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2007] [Accepted: 10/30/2007] [Indexed: 11/19/2022]
Abstract
Cell activation or apoptosis leads to plasma membrane blebbing and microparticles (MPs) release in the extracellular space. MPs are submicron membrane vesicles, which harbour a panel of oxidized phospholipids and proteins specific to the cells they derived from. MPs are found in the circulating blood of healthy volunteers. MPs levels are increased in many diseases, including cardiovascular diseases with high thrombotic risk. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. Elevation of plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and appears now as a surrogate marker of vascular dysfunction. Recent studies demonstrate an elevation of circulating levels of MPs in diabetes. MPs could also be involved in the development of vascular complications in diabetes for they stimulate pro-inflammatory responses in target cells and promote thrombosis, endothelial dysfunction and angiogenesis. Thus, these studies provide new insight in the pathogenesis and treatment of vascular complications of diabetes.
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Affiliation(s)
- A S Leroyer
- Institut National de la Santé et de la Recherche Médicale, Inserm unit 689, Cardiovascular Research Center Inserm Lariboisière, 41, bd de la Chapelle, 75475 Paris cedex 10, France
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40
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Abstract
Cell activation or apoptosis leads to plasma membrane blebbing and microparticle (MP) release in the extracellular space. MPs are submicron membrane vesicles which express a panel of phospholipids and proteins specific of the cells they are derived from. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. MPs accumulate in the lipid core of the atherosclertotic plaque and is a major determinant of its thrombogenecity. Elevation of plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and is considered now as a surrogate marker of vascular dysfunction. Thus, MPs can be seen as triggers of a vicious circle for they promote prothrombogenic and pro-inflammatory responses as well as cellular dysfunction within the vascular compartment. A better knowledge of MP composition and biological effects as well as the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.
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Affiliation(s)
- A S Leroyer
- Institut National de la Santé et de la Recherche Médicale (Unit 689), Cardiovascular Research Institute Inserm, Paris, France
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41
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El Haouari M, Rosado JA. Platelet signalling abnormalities in patients with type 2 diabetes mellitus: a review. Blood Cells Mol Dis 2008; 41:119-23. [PMID: 18387322 DOI: 10.1016/j.bcmd.2008.02.010] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2008] [Accepted: 02/27/2008] [Indexed: 11/29/2022]
Abstract
The hyperactivation of platelets is involved in the cardiovascular complications associated with type 2 diabetes mellitus. Altered platelet behavior contributes to the angiopathies associated with diabetes. A number of mechanisms involved in platelet activation are altered in diabetes. Platelets from type 2 diabetic patients show an enhanced endogenous reactive oxygen species production and a reduced antioxidant capability, which increase the activity of several tyrosine kinases, such as the Bruton's tyrosine kinase, MAP kinases or proteins of the SRC family. Oxidative stress is also involved in the abnormal intracellular calcium homeostasis observed in platelets from type 2 diabetics, including an enhanced resting cytosolic calcium concentration and calcium release and entry in response to agonists. Moreover, diabetes alters the bioavailability of nitric oxide in platelets. Basal nitric oxide synthase activity is reduced in homogenates of platelets obtained from patients with type 2 diabetes mellitus. The study of these abnormalities might be helpful in the development of new pharmacological strategies to reduce platelet activation in type 2 diabetes mellitus.
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Affiliation(s)
- Mohammed El Haouari
- Laboratoire de Physiologie et d'Ethnopharmacologie, Département de Biologie, Université Mohamed 1er, Faculté des Sciences, Bd. Mohamed VI, BP 717, Oujda 60000, Morocco
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Abstract
Thrombosis remains one of the leading causes of mortality and morbidity in developed countries. Relevant markers of the primary thrombotic risk however remain of limited accessibility, and clinicians are left with markers of essentially etiological nature. Fortunately, new entities, testifying to cellular activation or damage within the vascular compartment, have been recently described and are in the validation process. Microparticles (MP) are plasma membrane fragments released by stimulated or apoptotic cells. In the vascular compartment, they constitute a disseminated storage pool of bioactive effectors involved in inflammation, thrombosis, vascular tone, angiogenesis. Their biological characteristics are predetermined by the cytosolic and membraneous components hijacked from the activated cells. Their procoagulant properties are based on, (i) the accessibility of phosphatidylserine, a procoagulant aminophospholipid exposed after stimulation and necessary for the assembly of the blood clotting enzyme complexes, and (ii) the possible presence of tissue factor, the major initiator of the coagulation cascade. The incidence of MP in haemostatic processes has been demonstrated in physiology and pathology. They are now considered true pathogenic markers of the thrombotic risk.
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Affiliation(s)
- O Morel
- Unité 143 Inserm, Hôpital de Bicêtre, France
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43
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Lösche W, Heptinstall S. Value of Platelet Activation Markers as Prothrombotic Risk Indicators. Transfus Med Hemother 2007. [DOI: 10.1159/000097497] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Morel O, Toti F, Hugel B, Bakouboula B, Camoin-Jau L, Dignat-George F, Freyssinet JM. Procoagulant Microparticles. Arterioscler Thromb Vasc Biol 2006; 26:2594-604. [PMID: 16990554 DOI: 10.1161/01.atv.0000246775.14471.26] [Citation(s) in RCA: 350] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Apoptosis and vascular cell activation are main contributors to the release of procoagulant microparticles (MPs), deleterious partners in atherothrombosis. Elevated levels of circulating platelet, monocyte, or endothelial-derived MPs are associated with most of the cardiovascular risk factors and appear indicative of poor clinical outcome. In addition to being a valuable hallmark of vascular cell damage, MPs are at the crossroad of atherothrombosis processes by exerting direct effects on vascular or blood cells. Under pathological circumstances, circulating MPs would support cellular cross-talk leading to vascular inflammation and tissue remodeling, endothelial dysfunction, leukocyte adhesion, and stimulation. Exposed membrane phosphatidylserine and functional tissue factor (TF) are 2 procoagulant entities conveyed by circulating MPs. At sites of vascular injury, P-selectin exposure by activated endothelial cells or platelets leads to the rapid recruitment of MPs bearing the P-selectin glycoprotein ligand-1 and blood-borne TF, thereby triggering coagulation. Within the atherosclerotic plaque, sequestered MPs constitute the main reservoir of TF activity, promoting coagulation after plaque erosion or rupture. Lesion-bound MPs, eventually harboring proteolytic and angiogenic effectors are additional actors in plaque vulnerability. Pharmacological strategies aimed at modulating the release of procoagulant MPs appear a promising therapeutic approach of both thrombotic processes and bleeding disorders.
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Affiliation(s)
- Olivier Morel
- Université Louis Pasteur, Faculté de Médecine, Institut d'Hématologie et d'Immunologie, Strasbourg, France
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45
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Morel N, Morel O, Delabranche X, Jesel L, Sztark F, Dabadie P, Freyssinet JM, Toti F. [Microparticles during sepsis and trauma. A link between inflammation and thrombotic processes]. ACTA ACUST UNITED AC 2006; 25:955-66. [PMID: 16926090 DOI: 10.1016/j.annfar.2006.04.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2005] [Accepted: 04/13/2006] [Indexed: 12/26/2022]
Abstract
Sepsis and trauma lead to a sustained activation of monocytes and endothelium. In the vascular compartment, stimulated cells release microparticles. Circulating MP provide an additional procoagulant phospholipid surface enabling the assembly of the clotting enzymes complexes and thrombin generation. Their procoagulant properties rely on the exposition of phosphatidylserine, made accessible after cell stimulation and on the possible presence of tissue factor, the main cellular initiator of blood coagulation. Microparticles constitute the main reservoir of blood-borne tissue factor activity. At sites of endothelium injury, enhanced release or recruitment of procoagulant MP through P-selectin-PSGL-1 pathway could concentrate TF activity above a threshold allowing blood coagulation to be triggered. Converging evidences from experimental or clinical data highlight a role for MP harboring tissue factor in the initiation of disseminated intravascular coagulopathy. In these settings, the pharmacological modulation of MP levels or biological functions through activated protein C or factor VIIa allows challenging issues.
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Affiliation(s)
- N Morel
- Service d'urgences et de réanimation chirurgicale, hôpital Pellegrin, Bordeaux, France
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Morel O, Jesel L, Freyssinet JM, Toti F. Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis. Thromb J 2005; 3:15. [PMID: 16219103 PMCID: PMC1266401 DOI: 10.1186/1477-9560-3-15] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2005] [Accepted: 10/11/2005] [Indexed: 12/01/2022] Open
Abstract
Circulating procoagulant microparticles (MP) are pathogenic markers of enhanced coagulability associated to a variety of disorders and released from stimulated vascular cells. When derived from endothelial cells, MP were found characteristic of thrombotic propensity in primary antiphospholipid syndrome (APS). The prothrombotic status of a patient with antiphospholipid antibodies (APL), a past history of mesenteric vein thrombosis and presenting myocardial infarction and extensive intracardiac thrombosis was examined by measurement of circulating procoagulant MP. MP of platelet and endothelial origins were highly elevated with respect to values detectable in patients with myocardial infarction and no history of APS (6- and 3-fold elevation, respectively) or in healthy volunteers (13- and 25-fold elevation, respectively). In this particular patient, with moderate APL titer, a drastic release of procoagulant MP could have contributed to thrombus growth and the development of extensive intracardiac thrombosis.
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Affiliation(s)
- O Morel
- Fédération de Cardiologie des Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1 avenue Molière, 67098 Strasbourg, France
- Université Louis Pasteur, Faculté de Médecine, Institut d'Hématologie et d'Immunolgie, 4, rue Kirschleger, 67085 Strasbourg, France
- Unité 143 INSERM, Hôpital de Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France
| | - L Jesel
- Fédération de Cardiologie des Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1 avenue Molière, 67098 Strasbourg, France
| | - JM Freyssinet
- Université Louis Pasteur, Faculté de Médecine, Institut d'Hématologie et d'Immunolgie, 4, rue Kirschleger, 67085 Strasbourg, France
- Unité 143 INSERM, Hôpital de Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France
| | - F Toti
- Université Louis Pasteur, Faculté de Médecine, Institut d'Hématologie et d'Immunolgie, 4, rue Kirschleger, 67085 Strasbourg, France
- Unité 143 INSERM, Hôpital de Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France
- Université Paris-Sud, Faculté de Médecine, 63 rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France
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Morel O, Ohlmann P, Jesel L, Morel N, Ridard C, Faure A, Grunebaum L, Toti F, Bareiss P. [Variable extent of platelet responsiveness to clopidogrel inhibition: "clopidogrel resistance"?]. Ann Cardiol Angeiol (Paris) 2005; 54:194-200. [PMID: 16104620 DOI: 10.1016/j.ancard.2005.05.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
During percutaneous coronary angioplasty, platelet inhibition by clopidogrel and aspirin has drastically decreased the risk of thrombotic occlusion of the stented vessels. However, despite the widespread use of these drugs, the incidence of acute or subacute stent thrombosis remains elevated, concerning 1 to 2% of the treated patients. Considerable differences in the responsiveness to clopidogrel could be observed, suggesting a possible underlying biological resistance. "Clopidogrel resistance" has recently been associated to an increased risk of thrombotic events following coronary angioplasty. Variations in enteric absorption, biotransformation in the liver by the CYP3A4, changes in the ADP receptor P2Y12, abnomalies of intraplatelet signal transduction, extent of platelet activation, class angina, diabetes mellitus may account for the considerable interindividual response variability widely reported. In this view, laboratory tests evaluating "clopidogrel resistance" might be useful tools for the identification and follow-up of patients at higher thrombotic risk. Indeed, in these patients, further platelet inhibition can be achieved by higher doses of clopidogrel.
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Affiliation(s)
- O Morel
- Fédération de cardiologie des hôpitaux universitaires de Strasbourg, France.
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Affiliation(s)
- G Davì
- Center of Excellence on Aging, G. d'Annunzio University Foundation, Chieti, Italy.
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Morel O, Toti F, Hugel B, Freyssinet JM. Cellular microparticles: a disseminated storage pool of bioactive vascular effectors. Curr Opin Hematol 2005; 11:156-64. [PMID: 15257014 DOI: 10.1097/01.moh.0000131441.10020.87] [Citation(s) in RCA: 229] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Microparticles (MP) or microvesicles are fragments shed from the plasma membrane of stimulated or apoptotic cells. Having long been considered inert debris reflecting cellular activation or damage, MP are now acknowledged as cellular effectors involved in cell-cell crosstalk. This review focuses on procoagulant MP circulating in the vascular compartment, their role in hemostasis and thrombosis, and possible impact in vascular functions. RECENT FINDINGS Microparticles can be viewed as a "storage pool" by themselves, disseminating blood-borne tissue factor activity and procoagulant phospholipids. Increasing evidences of integrated loops involving dynamic exchanges and transfer events through multiple MP-cell interactions are summarized. SUMMARY Microparticles can be considered true targets in the pharmacological control of thrombosis. Another challenging issue is to take advantage of their procoagulant potential for the management of hemophilia.
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Affiliation(s)
- Olivier Morel
- Institut d'Hématologie et d'Immunolgie, Faculté de Médecine, Université Louis Pasteur, 4 rue Kirschleger, 67085 Strasbourg Cedex, France
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Jimenez JJ, Jy W, Mauro LM, Horstman LL, Bidot CJ, Ahn YS. Endothelial Microparticles (EMP) as Vascular Disease Markers. Adv Clin Chem 2005; 39:131-57. [PMID: 16013670 DOI: 10.1016/s0065-2423(04)39005-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Joaquin J Jimenez
- Department of Medicine, Division of Hematology Oncology, Wallace H. Coulter Platelet Laboratory, University of Miami School of Medicine, Miami, Florida 33136, USA
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