Exp Mol Med.
2007 Apr;39(2):160-169.
A point mutant of apolipoprotein A-I, V156K, exhibited potent anti-oxidant and anti-atherosclerotic activity in hypercholesterolemic C57BL/6 mice
- Affiliations
-
- 1School of Biotechnology and Aging-associated Vascular Disease Research Center Yeungnam University Gyeongsan 712-749, Korea. chok@yu.ac.kr
- 2Laboratory of Lipid Metabolism, Korea Research Institute of Bioscience and Biotechnology Daejeon 305-333, Korea.
- 3Laboratory of Experimental Animal, Korea Research Institute of Bioscience and Biotechnology Daejeon 305-333, Korea.
- 4Department of Food and Nutrition, Chungnam National University, Daejeon 305-764, Korea.
- 5Department of Biochemistry and Molecular Biology, Aging-associated Vascular Disease Research Center, Yeungnam University, Daegu 705-717, Korea.
Abstract
- In our previous study, two point mutants of apolipoprotein A-I, designated V156K and A158E, revealed peculiar characteristics in their lipid-free and lipid-bound states. In order to determine the putative therapeutic potential of these mutants, several in vitro and in vivo evaluations were conducted. In the lipid-free state, V156K showed more profound antioxidant activity against LDL oxidation than did the wildtype (WT) or A158E variants in an in vitro assay. In the lipid-bound state, V156K-rHDL showed an enhanced cholesterol delivery activity to HepG2 cells in a time-dependent manner, as compared to WT-rHDL, A158E-rHDL, and R173C-rHDL. We assessed the physiological activities of the mutants in circulation, using hypercholesterolemic mice (C57BL6/J). Palmitoyloleoyl phosphatidylcholine (POPC)-rHDL preparations containing each of the apoA-I variants were injected into the mice at a dosage of 30 mg of apoA-I/kg of body weight. Forty eight hours after injection, the sera of the V156K-rHDL injected group showed the most potent antioxidant abilities in the ferric acid removal assay. The V156K-rHDL- or R173C-rHDL-injected mice showed no atherosclerotic lesions and manifested striking increases in their serum apo-E levels, as compared to the mice injected with WT-rHDL or A158E-rHDL. In conclusion, V156K-rHDL exhibited the most pronounced antioxidant activity and anti-atherosclerotic activity, both in vitro and in vivo. These results support the notion that HDL-therapy may prove beneficial due to its capacity to induce accelerated cholesterol excretion, as well as its enhanced antioxidant and anti-inflammatory effects and lesion regression effect.
MeSH Terms
-
Amino Acids/*genetics
Animals
Antioxidants/*metabolism
Apolipoprotein A-I/*genetics
Atherosclerosis/*pathology
Biological Transport/drug effects
Cell Line, Tumor
Cholesterol/metabolism
Copper/pharmacology
Humans
Hypercholesterolemia/chemically induced/*pathology
Lipoproteins, HDL/blood
Lipoproteins, LDL/blood
Male
Mice
Mice, Inbred C57BL
Oxidation-Reduction/drug effects
Point Mutation/*genetics
Recombinant Proteins/blood
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