title: Trimerization of apolipoprotein A-I retards plasma clearance and preserves antiatherosclerotic properties.
abstract: An increased plasma level of the major high-density lipoprotein (HDL) component, apolipoprotein A-I (apoA-I) is the aim of several therapeutic strategies for combating atherosclerotic disease. HDL therapy by direct intravenous administration of apoA-I is a plausible way; however, a fast renal filtration is a major obstacle for this approach. Using protein engineering technology, we have fused apoA-I to the trimerization domain of human tetranectin and thus constructed a high-mass recombinant trimeric apoA-I variant. The recombinant fusion protein was stable and expressed well; upon purification and intravenous injection into mice, it exhibited prolonged plasma retention time compared to wild type apoA-I. Trimeric apoA-I was biologically active in terms of promoting cholesterol efflux, stimulation of lecithin cholesterol acyltransferase-mediated cholesterol esterification, and reducing progression of atherosclerosis in cholesterol-fed low-density lipoprotein receptor-deficient mice. Direct administration of recombinant high-mass apoA-I analogues with retarded clearance is therefore a potential novel therapeutic approach for atherosclerotic plaque stabilization.
authors.affiliation: ProteoPharma ApS and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
authors.forename: Jonas Heilskov
authors.initials: JH
authors.lastname: Graversen
authors.forename: Jacob Marsvin
authors.initials: JM
authors.lastname: Laurberg
authors.forename: Mikkel Holmen
authors.initials: MH
authors.lastname: Andersen
authors.forename: Erling
authors.initials: E
authors.lastname: Falk
authors.forename: John
authors.initials: J
authors.lastname: Nieland
authors.forename: Jesper
authors.initials: J
authors.lastname: Christensen
authors.forename: Michael
authors.initials: M
authors.lastname: Etzerodt
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Thøgersen
authors.forename: Søren Kragh
authors.initials: SK
authors.lastname: Moestrup
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011108:Polymers; D011973:Receptors, LDL / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D011108:Polymers; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D002784:Cholesterol