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      Message in a Microbottle: Modulation of Vascular Inflammation and Atherosclerosis by Extracellular Vesicles

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          Abstract

          Extracellular vesicles (EVs) have emerged as a novel intercellular communication system. By carrying bioactive lipids, miRNAs and proteins they can modulate target cell functions and phenotype. Circulating levels of EVs are increased in inflammatory conditions, e.g., cardiovascular disease patients, and their functional contribution to atherosclerotic disease development is currently heavily studied. This review will describe how EVs can modulate vascular cell functions relevant to vascular inflammation and atherosclerosis, particularly highlighting the role of EV-associated proteolytic activity and effector proteins involved. Furthermore, we will discuss key questions and challenges, especially for EV-based therapeutics.

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          Most cited references 83

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          Extracellular vesicles: Exosomes, microvesicles, and friends

          Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.
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            Inflammation and atherosclerosis.

            Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
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              Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.

              To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/229058
                URI : http://frontiersin.org/people/u/406865
                Journal
                Front Cardiovasc Med
                Front Cardiovasc Med
                Front. Cardiovasc. Med.
                Frontiers in Cardiovascular Medicine
                Frontiers Media S.A.
                2297-055X
                22 January 2018
                2018
                : 5
                Affiliations
                1DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich, Germany
                2Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich , Munich, Germany
                3Center of Allergy Environment (ZAUM), Helmholtz Center, TU Munich , Neuherberg, Germany
                4Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, Netherlands
                Author notes

                Edited by: Rory R. Koenen, Maastricht University, Netherlands

                Reviewed by: Bernhard H. Rauch, University of Greifswald, Germany; Christina Bursill, South Australian Health and Medical Research Institute, Australia; Teresa Padro, Centre d’Investigació Cardiovascular (CSIC), Spain

                *Correspondence: Emiel P. C. van der Vorst, emiel.van_der_vorst@ 123456med.uni-muenchen.de ; Marjo M. P. C. Donners, marjo.donners@ 123456maastrichtuniversity.nl

                Specialty section: This article was submitted to Atherosclerosis and Vascular Medicine, a section of the journal Frontiers in Cardiovascular Medicine

                Article
                10.3389/fcvm.2018.00002
                5786527
                Copyright © 2018 van der Vorst, de Jong and Donners.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 1, Tables: 1, Equations: 0, References: 83, Pages: 8, Words: 6371
                Categories
                Cardiovascular Medicine
                Mini Review

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