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.