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J Cardiovasc Pharmacol. 2008 Feb;51(2):170-7. doi: 10.1097/FJC.0b013e31815ed0b9.

Trimerization of apolipoprotein A-I retards plasma clearance and preserves antiatherosclerotic properties.

Author information

1
ProteoPharma ApS and Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.

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.

PMID:
18287885
DOI:
10.1097/FJC.0b013e31815ed0b9
[Indexed for MEDLINE]

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