A reconstituted high density lipoprotein containing the V156E mutant of apolipoprotein A-I exhibits anti-atherosclerotic activity in apo-E deficient mice

Abstract

Aim: A point mutation of apolipoprotein A-I, V156E, is naturally occurring and is found in Oita, Japan. V156E of apoA-I (apoA-Ioita) shows unique structural and functional properties and more potent antioxidant activity against copper-mediated low-density lipoprotein (LDL) oxidation in vitro. Methods: A reconstituted high-density lipoprotein (rHDL)-containing V156E (V156E-rHDL) suppressed the accumulation of [3H]-cholesteryl ester (CE)-LDL in THP-1 cells. To compare the short-term anti-atherosclerotic effects of V156E and wild-type (WT) apo A-I, palmitoyloleoyl phosphatidylcholine (POPC)-rHDL-containing V156E or WT was infused into atherosclerotic apo-E-deficient mice. Each POPC-rHDL was injected via the tail vein at a dosage of 150 mg/kg body weight in 0.4 mL Tris-buffered saline (TBS), and blood was collected 24 and 48 hours post-injection. Results: Serum interleukin (IL)-6 levels were decreased 28% in the V156E-rHDL group 48 hours post-injection. Injection with V156E-rHDL induced a reduction of the lipid-stained area in lesions by 26% and the number of macrophages detected in the lesions was decreased by 40% compared to with WT-rHDL injection. Serum lecithin:cholesterol acyltransferase and paraoxonase activity was enhanced in V156E-rHDL-injected mice. The antioxidant ability in the ferric reduced ability serum assay was also increased in the V156E group at both 24 and 48 hours post-injection, with a decrease of serum lipid hydroperoxide concentration. Conclusion: Blood infusion of V156E-rHDL resulted in potent lesion regression activity and enhanced anti-inflammatory and antioxidant activities in apo-E deficient mice compared to the WT-rHDL group. These results provide evidence suggesting that V156E-apoA-I may be a good candidate for HDL therapy.