title: Impaired Endothelial Regeneration Through Human Parvovirus B19-Infected Circulating Angiogenic Cells in Patients With Cardiomyopathy.
abstract: Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage.
authors: Department of Cardiology and Pneumology Berlin-Brandenburg Center for Regenerative Therapies Medico-Academic Consultings.
authors: Caroline
authors: C
authors: Schmidt-Lucke
authors: Department of Cardiology and Pneumology.
authors: Thomas
authors: T
authors: Zobel
authors: Transplant and Stem Cell Immunobiology Laboratory, University Heart Center Hamburg.
authors: Sonja
authors: S
authors: Schrepfer
authors: Department of Cardiology and Pneumology.
authors: Uwe
authors: U
authors: Kuhl
authors: Transplant and Stem Cell Immunobiology Laboratory, University Heart Center Hamburg.
authors: Dong
authors: D
authors: Wang
authors: Department of Molecular Pathology, Institute of Pathology, Tübingen, Germany.
authors: Karin
authors: K
authors: Klingel
authors: Department of Cardiology and Pneumology.
authors: Peter Moritz
authors: PM
authors: Becher
authors: Department of Cardiology and Pneumology Institute for Biotechnology, University of Technology.
authors: Henry
authors: H
authors: Fechner
authors: Department of Cardiology and Pneumology.
authors: Tanja
authors: T
authors: Pozzuto
authors: Department of Cardiology and Pneumology.
authors: Sophie
authors: S
authors: Van Linthout
authors: Institut für kardiale Diagnostik und Therapie.
authors: Dirk
authors: D
authors: Lassner
authors: Department of Cardiology and Pneumology.
authors: Frank
authors: F
authors: Spillmann
authors: Department of Cardiology and Pneumology.
authors: Felicitas
authors: F
authors: Escher
authors: Department of Cardiovascular Surgery.
authors: Sebastian
authors: S
authors: Holinski
authors: Institute of Medical Immunology, Charité-Universitätsmedizin Berlin-Brandenburg Center for Regenerative Therapies.
authors: Hans-Dieter
authors: HD
authors: Volk
authors: Department of Cardiology and Pneumology.
authors: Heinz-Peter
authors: HP
authors: Schultheiss
authors: Department of Cardiology and Pneumology Berlin-Brandenburg Center for Regenerative Therapies Deutsches Zentrum für Herz-Kreislauf-Forschung, Berlin.
authors: Carsten
authors: C
authors: Tschope
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000150:complications*; D016022:Case-Control Studies; D053455:Caspase 10 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000502:physiology / Q000821:virology; D016731:Erythema Infectiosum / Q000821:virology*; D015672:Erythroid Precursor Cells / Q000502:physiology / Q000821:virology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D016732:Parvovirus B19, Human / Q000235:genetics / Q000502:physiology*; D012038:Regeneration; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; D053455:Caspase 10; C506438:CASP10 protein, human
keywords: apoptosis; endothelial progenitor cells; endothelial regeneration; reendothelialization; viruses