Characteristics and Roles of Exosomes in Cardiovascular Disease.

Exosomes are nano-sized biological membrane-enclosed vesicles that contain a cell-specific cargo of proteins, lipids, and nucleic acids that are released and taken up by most cell types, thereby inducing expression and functional changes via horizontal transfer of cargos between cells. Thus, exosomes present a largely unknown "cell-to-cell" communication system, which is now increasingly being investigated for diagnostic and therapeutic use in cardiovascular disease (CVD). The purpose of this review is to summarize recent findings on the properties and roles of exosomes in a variety of physiological and pathological settings related to CVD. We focus on available information on exosome-mediated intercellular communication relevant to myocardial injury, repair, and regeneration. Finally, we address the promise of exosomes as valuable diagnostic and prognostic biomarkers, and their potential use as therapeutic tools in CVD. Exosomes remain largely unexplored for therapeutic use in the field of cardiovascular diagnosis and medicine. A more detailed characterization of cardiac exosomes shed by different components of the heart will be of fundamental importance to address specific changes in the profile of exosomal microRNAs and proteins, which will enable the clinical use of exosomes as minimally invasive diagnostic tools and vehicles for delivery of targeted therapies for CVD.

[1]  H. Iwao,et al.  Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction. , 2015, International journal of cardiology.

[2]  A. Knowlton,et al.  HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. , 2007, American journal of physiology. Heart and circulatory physiology.

[3]  A. Fomina,et al.  T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor , 2007, Journal of cellular physiology.

[4]  Chen-Yu Zhang,et al.  Extracellular Vesicles: Novel Mediators of Cell Communication In Metabolic Disease , 2017, Trends in Endocrinology & Metabolism.

[5]  I. Komuro,et al.  Circulating p53-Responsive MicroRNAs Are Predictive Indicators of Heart Failure After Acute Myocardial Infarction , 2013, Circulation research.

[6]  E. Olson,et al.  MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca²⁺ overload and cell death. , 2012, The Journal of clinical investigation.

[7]  P. Doevendans,et al.  Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells , 2010, Journal of cellular and molecular medicine.

[8]  S. Gabrielsson,et al.  Exosomes from breast milk inhibit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4+ T cells , 2014, AIDS.

[9]  U. Markert,et al.  Extracellular vesicles in blood, milk and body fluids of the female and male urogenital tract and with special regard to reproduction , 2016, Critical reviews in clinical laboratory sciences.

[10]  Xiaohong Wang,et al.  Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis , 2015, Scientific Reports.

[11]  M. Mayr,et al.  Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. , 2015, Circulation research.

[12]  K. Tsuda Plasma Homocysteine Levels and Endothelial Dysfunction in Cerebro- and Cardiovascular Diseases in the Metabolic Syndrome. , 2015, American journal of hypertension.

[13]  B. Li,et al.  A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. , 2015, Journal of molecular and cellular cardiology.

[14]  M. Ashraf,et al.  Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. , 2013, Biochemical and biophysical research communications.

[15]  R. Kishore,et al.  Sonic Hedgehog–Modified Human CD34+ Cells Preserve Cardiac Function After Acute Myocardial Infarction , 2012, Circulation research.

[16]  G. Szabo,et al.  Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. , 2014, Nanomedicine : nanotechnology, biology, and medicine.

[17]  J. Ge,et al.  Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway , 2016, Journal of cellular and molecular medicine.

[18]  Z. Giricz,et al.  Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. , 2014, Journal of molecular and cellular cardiology.

[19]  Xiang Cheng,et al.  Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia , 2016, Journal of Molecular Medicine.

[20]  K. Sliwa,et al.  MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. , 2013, The Journal of clinical investigation.

[21]  M. Kuroda,et al.  Exosome-Mediated Targeted Delivery of miRNAs. , 2016, Methods in molecular biology.

[22]  Chunxiang Zhang,et al.  A translational study of urine miRNAs in acute myocardial infarction. , 2012, Journal of molecular and cellular cardiology.

[23]  S. Hazen,et al.  A CD36‐dependent signaling cascade is necessary for macrophage foam cell formation , 2006, Cell metabolism.

[24]  Xiaoke Yin,et al.  Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. , 2014, The Journal of clinical investigation.

[25]  Alireza Ahadi,et al.  Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes , 2016, Scientific Reports.

[26]  G. Ronquist,et al.  Role of exosomes in myocardial remodeling. , 2014, Circulation research.

[27]  Gerard Pasterkamp,et al.  Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. , 2013, Stem cell research.

[28]  R. Johnstone,et al.  Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). , 1987, The Journal of biological chemistry.

[29]  R. Ferrari,et al.  CD34+ and Endothelial Progenitor Cells in Patients With Various Degrees of Congestive Heart Failure , 2004, Circulation.

[30]  M. Wood,et al.  Exosomes and the blood-brain barrier: implications for neurological diseases. , 2011, Therapeutic delivery.

[31]  Q. Han,et al.  Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a , 2016, Journal of Cell Science.

[32]  Monika Pietrowska,et al.  Proteomic analysis of exosomal cargo: the challenge of high purity vesicle isolation. , 2016, Molecular bioSystems.

[33]  M. Mayr,et al.  Novel methodologies for biomarker discovery in atherosclerosis. , 2015, European heart journal.

[34]  T. McIntyre,et al.  Exosome poly‐ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro‐atherothombotic cellular functions , 2014, Journal of thrombosis and haemostasis : JTH.

[35]  M. Matthay,et al.  Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. , 2012, American journal of physiology. Lung cellular and molecular physiology.

[36]  Toshihiro Tamura,et al.  Increased MicroRNA-1 and MicroRNA-133a Levels in Serum of Patients With Cardiovascular Disease Indicate Myocardial Damage , 2011, Circulation. Cardiovascular genetics.

[37]  Shivakumar Keerthikumar,et al.  ExoCarta: A Web-Based Compendium of Exosomal Cargo. , 2016, Journal of molecular biology.

[38]  Achilleas S. Frangakis,et al.  Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs , 2012, Nature Cell Biology.

[39]  G. Angelini,et al.  Exosomes and exosomal miRNAs in cardiovascular protection and repair. , 2015, Vascular pharmacology.

[40]  Takuya Hayashi,et al.  Circulating CD34-Positive Cells Provide an Index of Cerebrovascular Function , 2004, Circulation.

[41]  K. Webster,et al.  Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA‐21 , 2016, Stem cells translational medicine.

[42]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[43]  Heinrich J. Huber,et al.  Exosomes: emerging roles in communication between blood cells and vascular tissues during atherosclerosis , 2015, Current opinion in lipidology.

[44]  Thomas Würdinger,et al.  Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. , 2013, Blood.

[45]  U. Gezer,et al.  Long non‐coding RNAs with low expression levels in cells are enriched in secreted exosomes , 2014, Cell biology international.

[46]  Dongmei Sun,et al.  A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[47]  M. Feinberg,et al.  Regulation of endothelial cell metabolism: just go with the flow. , 2015, Arteriosclerosis, thrombosis, and vascular biology.

[48]  R. Gladstone,et al.  MicroRNA-144 is a circulating effector of remote ischemic preconditioning , 2014, Basic Research in Cardiology.

[49]  Gerard Pasterkamp,et al.  Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. , 2010, Stem cell research.

[50]  J. Vicencio,et al.  Plasma exosomes protect the myocardium from ischemia-reperfusion injury. , 2015, Journal of the American College of Cardiology.

[51]  K. Ohyashiki,et al.  Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. , 2014, Blood.

[52]  Joel Stein,et al.  Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. , 2014, Circulation.

[53]  E. Bassi,et al.  Platelet-derived exosomes from septic shock patients induce myocardial dysfunction , 2007, Critical care.

[54]  Yoshihiro Sasaki,et al.  Engineering hybrid exosomes by membrane fusion with liposomes , 2016, Scientific Reports.

[55]  K. Sliwa,et al.  A Cathepsin D-Cleaved 16 kDa Form of Prolactin Mediates Postpartum Cardiomyopathy , 2007, Cell.

[56]  R. Schiffelers,et al.  Exosome mimetics: a novel class of drug delivery systems , 2012, International journal of nanomedicine.

[57]  Jiang Chang,et al.  Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. , 2014, Journal of molecular and cellular cardiology.

[58]  P. Ferdinandy,et al.  Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. , 2010, Cardiovascular research.

[59]  P. Jones,et al.  Exosomes in human semen restrict HIV-1 transmission by vaginal cells and block intravaginal replication of LP-BM5 murine AIDS virus complex. , 2015, Virology.

[60]  D. Meldrum,et al.  Intravenous Infusion of Mesenchymal Stem Cells Is Associated With Improved Myocardial Function During Endotoxemia , 2011, Shock.

[61]  I. Nakano,et al.  miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients , 2015, Journal of Neuro-Oncology.

[62]  M. Record,et al.  Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. , 2014, Biochimica et biophysica acta.

[63]  Y. Gho,et al.  Proteomics of extracellular vesicles: Exosomes and ectosomes. , 2015, Mass spectrometry reviews.

[64]  G. Pasterkamp,et al.  Derivation and characterization of human fetal MSCs: an alternative cell source for large-scale production of cardioprotective microparticles. , 2010, Journal of molecular and cellular cardiology.

[65]  Yu Qin,et al.  STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells. , 2016, Cancer letters.

[66]  G. Lip,et al.  Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis , 2010, Journal of thrombosis and haemostasis : JTH.

[67]  Kristin M. French,et al.  Identification of Therapeutic Covariant MicroRNA Clusters in Hypoxia-Treated Cardiac Progenitor Cell Exosomes Using Systems Biology , 2015, Circulation research.

[68]  Xue Leng,et al.  Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes. , 2009, Biochemical and biophysical research communications.

[69]  E. Solary,et al.  Gap junction-mediated transfer of miR-145-5p from microvascular endothelial cells to colon cancer cells inhibits angiogenesis , 2016, Oncotarget.

[70]  M. Janiszewski,et al.  Platelet-derived exosomes induce endothelial cell apoptosis through peroxynitrite generation: experimental evidence for a novel mechanism of septic vascular dysfunction , 2007, Critical care.