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


CONCLUSIONS
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.
Cho
Kyung-Hyun
KH
School of Biotechnology, Aging-Associated Vascular Disease Research Center, Yeungnam University, Gyeongsan 7712-749, South Korea. chok@yu.ac.kr
D000818:Animals; D000975:Antioxidants; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics*; D007249:Inflammation / Q000188:drug therapy; D007564:Japan; D008075:Lipoproteins, HDL / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D020125:Mutation, Missense; D011994:Recombinant Proteins
D000975:Antioxidants; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D050505:Mutant Proteins; D011994:Recombinant Proteins