title: Structural and functional characterization of endothelial microparticles released by cigarette smoke.
abstract: Circulating endothelial microparticles (EMPs) are emerging as biomarkers of chronic obstructive pulmonary disease (COPD) in individuals exposed to cigarette smoke (CS), but their mechanism of release and function remain unknown. We assessed biochemical and functional characteristics of EMPs and circulating microparticles (cMPs) released by CS. CS exposure was sufficient to increase microparticle levels in plasma of humans and mice, and in supernatants of primary human lung microvascular endothelial cells. CS-released EMPs contained predominantly exosomes that were significantly enriched in let-7d, miR-191; miR-126; and miR125a, microRNAs that reciprocally decreased intracellular in CS-exposed endothelium. CS-released EMPs and cMPs were ceramide-rich and required the ceramide-synthesis enzyme acid sphingomyelinase (aSMase) for their release, an enzyme which was found to exhibit significantly higher activity in plasma of COPD patients or of CS-exposed mice. The ex vivo or in vivo engulfment of EMPs or cMPs by peripheral blood monocytes-derived macrophages was associated with significant inhibition of efferocytosis. Our results indicate that CS, via aSMase, releases circulating EMPs with distinct microRNA cargo and that EMPs affect the clearance of apoptotic cells by specialized macrophages. These targetable effects may be important in the pathogenesis of diseases linked to endothelial injury and inflammation in smokers.
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|National Jewish Health, Denver, CO, USA.
authors.forename: Karina A
authors.initials: KA
authors.lastname: Serban
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Samin
authors.initials: S
authors.lastname: Rezania
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Daniela N
authors.initials: DN
authors.lastname: Petrusca
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Poirier
authors.affiliation: National Jewish Health, Denver, CO, USA.|Department of Biochemistry &Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Danting
authors.initials: D
authors.lastname: Cao
authors.affiliation: National Jewish Health, Denver, CO, USA.|Department of Biochemistry &Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Justice
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Patel
authors.affiliation: Departments of Biochemistry &Molecular Biology and Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Tsvetkova
authors.affiliation: Department of Biochemistry &Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamocki
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mikosz
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|National Jewish Health, Denver, CO, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Schweitzer
authors.affiliation: Departments of Biochemistry &Molecular Biology and Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Jacobson
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Cardoso
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.affiliation: Department of Pharmacology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Hubbard
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
authors.affiliation: Departments of Biochemistry &Molecular Biology and Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dragnea
authors.affiliation: National Jewish Health, Denver, CO, USA.|Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
authors.affiliation: Department of Biochemistry &Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: McClintock
authors.affiliation: The Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|National Jewish Health, Denver, CO, USA.|Richard L. Roudebush Veteran Affairs Medical Center, Indianapolis, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology; D012906:Smoke; D000074084:THP-1 Cells; D062789:Tobacco Products
chemical_list: D012906:Smoke