Gene transfer of extracellular superoxide dismutase to atherosclerotic mice.
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 in 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.
Laukkanen
M O
MO
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
Leppänen
P
P
Turunen
P
P
Porkkala-Sarataho
E
E
Salonen
J T
JT
Ylä-Herttuala
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D003300:Copper / Q000494:pharmacology; D004036:Diet, Atherogenic; D005822:Genetic Vectors; D006493:Heparin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D011973:Receptors, LDL / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000502:physiology*; D014018:Tissue Distribution; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D003300:Copper; D006493:Heparin; D013482:Superoxide Dismutase; D001616:beta-Galactosidase