Gene transfer of extracellular superoxide dismutase to atherosclerotic mice

被引:23
作者
Laukkanen, MO
Leppänen, P
Turunen, P
Porkkala-Sarataho, E
Salonen, JT
Ylä-Herttuala, S
机构
[1] Univ Kuopio, AI Virtanen Inst Mol Sci, FIN-70211 Kuopio, Finland
[2] Univ Kuopio, Res Inst Publ Hlth, FIN-70211 Kuopio, Finland
[3] Univ Kuopio, Dept Med, FIN-70211 Kuopio, Finland
关键词
D O I
10.1089/15230860152409040
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Clinical and epidemiological studies have provided circumstantial evidence that oxidized low-density lipoprotein (LDL) and antioxidants are involved in the pathogenesis of atherosclerosis. Superoxide dismutases (SODs) have been shown hi vitro to protect LDL from deleterious effects of superoxide anions. In the present study, we have used adenoviral gene transfer to determine effect of extracellular SOD (EC-SOD) on atherogenesis in LDL receptor -/- mice. Intravenous administration of EC-SOD adenovirus (2 X 10(9) plaque forming units) into tail vein targeted transgene mainly to liver and induced a 3.5- to sevenfold increase in plasma total SOD activity. EC-SOD was secreted into circulation for 2-3 weeks mostly in a truncated B-form, suggesting that endogenous proteolytic mechanisms control the level and distribution of the enzyme. Therapeutic potential was determined by measuring plasma resistance against copper oxidation and analyzing atherosclerotic lesion areas in aortas of LDL receptor -/- mice. Mice were kept on a cholesterol diet for 10 weeks before gene transfer and 3 or 6 weeks after the gene transfer. Results showed a tendency for a reduction in the overall lesion area after EC-SOD gene transfer as compared with LacZ transduced control mice, but the difference did not reach statistical significance. It is concluded that short-term overexpression of EC-SOD in vivo does not affect atherogenesis in LDL receptor -/- mice.
引用
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页码:397 / 402
页数:6
相关论文
共 26 条
[1]  
Adachi T, 1998, BIOL PHARM BULL, V21, P1090
[2]   Antiatherogenic effects of the antioxidant BO-653 in three different animal models [J].
Cynshi, O ;
Kawabe, Y ;
Suzuki, T ;
Takashima, Y ;
Kaise, H ;
Nakamura, M ;
Ohba, Y ;
Kato, Y ;
Tamura, K ;
Hayasaka, A ;
Higashida, A ;
Sakaguchi, H ;
Takeya, M ;
Takahashi, K ;
Inoue, K ;
Noguchi, N ;
Niki, E ;
Kodama, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (17) :10123-10128
[3]   NEW PERSPECTIVES ON THE BIOCHEMISTRY OF SUPEROXIDE ANION AND THE EFFICIENCY OF SUPEROXIDE DISMUTASES [J].
DEBY, C ;
GOUTIER, R .
BIOCHEMICAL PHARMACOLOGY, 1990, 39 (03) :399-405
[4]   The heparin-binding domain of extracellular superoxide dismutase is proteolytically processed intracellularly during biosynthesis [J].
Enghild, JJ ;
Thogersen, IB ;
Oury, TD ;
Valnickova, Z ;
Hojrup, P ;
Crapo, JD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (21) :14818-14822
[5]   THE ROLE OF LIPID-PEROXIDATION AND ANTIOXIDANTS IN OXIDATIVE MODIFICATION OF LDL [J].
ESTERBAUER, H ;
GEBICKI, J ;
PUHL, H ;
JURGENS, G .
FREE RADICAL BIOLOGY AND MEDICINE, 1992, 13 (04) :341-390
[6]   The in vitro and ex vivo antioxidant properties, and hypolipidemic activity of CGP 2881 [J].
Feldman, DL ;
Mogelesky, TC ;
Sharif, R ;
Sawyer, WK ;
Jeune, M ;
Hu, CW ;
Leonards, KS ;
Prescott, MF .
ATHEROSCLEROSIS, 1999, 144 (02) :343-355
[7]   SUPEROXIDE RADICAL AND SUPEROXIDE DISMUTASES [J].
FRIDOVICH, I .
ANNUAL REVIEW OF BIOCHEMISTRY, 1995, 64 :97-112
[8]   Vascular expression of extracellular superoxide dismutase in atherosclerosis [J].
Fukai, T ;
Galis, ZS ;
Meng, XP ;
Parthasarathy, S ;
Harrison, DG .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (10) :2101-2111
[9]  
Huber W, 1980, Agents Actions Suppl, V7, P185
[10]   MASSIVE XANTHOMATOSIS AND ATHEROSCLEROSIS IN CHOLESTEROL-FED LOW-DENSITY-LIPOPROTEIN RECEPTOR-NEGATIVE MICE [J].
ISHIBASHI, S ;
GOLDSTEIN, JL ;
BROWN, MS ;
HERZ, J ;
BURNS, DK .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (05) :1885-1893