title: Scavenger receptor class B, type I-mediated uptake of A1AT by pulmonary endothelial cells.
abstract: In addition to exerting a potent anti-elastase function, α-1 antitrypsin (A1AT) maintains the structural integrity of the lung by inhibiting endothelial inflammation and apoptosis. A main serpin secreted in circulation by hepatocytes, A1AT requires uptake by the endothelium to achieve vasculoprotective effects. This active uptake mechanism, which is inhibited by cigarette smoking (CS), involves primarily clathrin- but also caveola-mediated endocytosis and may require active binding to a receptor. Because circulating A1AT binds to high-density lipoprotein (HDL), we hypothesized that scavenging receptors are candidates for endothelial uptake of the serpin. Although the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) internalizes only elastase-bound A1AT, the scavenger receptor B type I (SR-BI), which binds and internalizes HDL and is modulated by CS, may be involved in A1AT uptake. Transmission electron microscopy imaging of colloidal gold-labeled A1AT confirmed A1AT endocytosis in both clathrin-coated vesicles and caveolae in endothelial cells. SR-BI immunoprecipitation identified binding to A1AT at the plasma membrane. Pretreatment of human lung microvascular endothelial cells with SR-B ligands (HDL or LDL), knockdown of SCARB1 expression, or neutralizing SR-BI antibodies significantly reduced A1AT uptake by 30-50%. Scarb1 null mice exhibited decreased A1AT lung content following systemic A1AT administration and reduced lung anti-inflammatory effects of A1AT supplementation during short-term CS exposure. In turn, A1AT supplementation increased lung SR-BI expression and modulated circulating lipoprotein levels in wild-type animals. These studies indicate that SR-BI is an important mediator of A1AT endocytosis in pulmonary endothelium and suggest a cross talk between A1AT and lipoprotein regulation of vascular functions.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana; anlocket@iu.edu.
authors.forename: Angelia D
authors.initials: AD
authors.lastname: Lockett
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana;
authors.forename: Daniela N
authors.initials: DN
authors.lastname: Petrusca
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Justice
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana;
authors.forename: Christophe
authors.initials: C
authors.lastname: Poirier
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana;
authors.forename: Karina A
authors.initials: KA
authors.lastname: Serban
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana;
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Rush
authors.affiliation: Division of Nephrology, Department of Medicine, Indiana University, Indianapolis, Indiana;
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kamocka
authors.affiliation: Department of Pharmacology, Rush University, Chicago, Illinois; and.
authors.forename: Dan
authors.initials: D
authors.lastname: Predescu
authors.affiliation: Department of Pharmacology, Rush University, Chicago, Illinois; and.
authors.forename: Sanda
authors.initials: S
authors.lastname: Predescu
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, Indiana; The Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana.
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051122:Scavenger Receptors, Class B / Q000502:physiology*; D012907:Smoking / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D000515:alpha 1-Antitrypsin
keywords: antiproteinase; cigarette smoke; lipoprotein; scavenger receptor; serpin