Trimerization of apolipoprotein A-I retards plasma clearance and preserves antiatherosclerotic properties.
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.
Graversen
Jonas Heilskov
JH
ProteoPharma ApS and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
Laurberg
Jacob Marsvin
JM
Andersen
Mikkel Holmen
MH
Falk
Erling
E
Nieland
John
J
Christensen
Jesper
J
Etzerodt
Michael
M
Thøgersen
Hans Christian
HC
Moestrup
Søren Kragh
SK
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
D016632:Apolipoprotein A-I; D011108:Polymers; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D002784:Cholesterol