title: Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes.
abstract: Upon local delivery, adenovirus (Ad) serotype 5 viruses use the coxsackie and Ad receptor (CAR) for cell binding and alpha(v) integrins for internalization. When administered systemically, however, their role in liver tropism is limited because CAR-permissive and mutated viruses show similar biodistribution, a finding recently attributed to blood coagulation factor (F) IX or complement protein C4BP binding to the adenovirus fiber and "bridging" to either low-density lipoprotein receptor-related protein or heparan sulfate proteoglycans. Here, we show that hepatocyte transduction in vitro can be enhanced by the vitamin K-dependent factors FX, protein C, and FVII in addition to FIX but not by prothrombin (FII), FXI, and FXII. This phenomenon was not dependent on proteolytic activation or cell signaling activity and for FX was mediated by direct virus-factor binding. Human FX substantially enhanced hepatocyte transduction by CAR-permissive and mutated viruses in an ex vivo liver perfusion model. In vivo, global down-regulation of vitamin K-dependent zymogens by warfarin significantly diminished liver uptake of CAR-deleted Ads; however, this phenomenon was fully rescued by acute infusion of human FX. Our results indicate a common and pivotal role for distinct vitamin K-dependent coagulation factors in mediating hepatocyte transduction by adenoviruses in vitro and in vivo.
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, 126 University Place, University of Glasgow, G12 8TA, United Kingdom.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.forename: Campbell G
authors.initials: CG
authors.lastname: Nicol
authors.forename: Dmitry M
authors.initials: DM
authors.lastname: Shayakhmetov
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Buckley
authors.forename: Laura
authors.initials: L
authors.lastname: Denby
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Kemball-Cook
authors.forename: Shaoheng
authors.initials: S
authors.lastname: Ni
authors.forename: Andre
authors.initials: A
authors.lastname: Lieber
authors.forename: John H
authors.initials: JH
authors.lastname: McVey
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D001779:Blood Coagulation Factors / Q000378:metabolism*; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004792:Enzyme Precursors / Q000378:metabolism; D005164:Factor IX / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005170:Factor X / Q000378:metabolism; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011991:Receptors, Virus / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic; D014812:Vitamin K / Q000378:metabolism*; D014859:Warfarin / Q000494:pharmacology
chemical_list: D001779:Blood Coagulation Factors; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004792:Enzyme Precursors; D011991:Receptors, Virus; D014812:Vitamin K; D014859:Warfarin; D005164:Factor IX; D005170:Factor X