Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice.
BACKGROUND
Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice.


RESULTS
Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2- to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively.


CONCLUSIONS
Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.
Department of Medicine, University of California, Los Angeles 90095-1679, USA.
Aaron
A
Tward
Yu-Rong
YR
Xia
Xu-Ping
XP
Wang
Yi-Shou
YS
Shi
Christina
C
Park
Lawrence W
LW
Castellani
Aldons J
AJ
Lusis
Diana M
DM
Shih
D000818:Animals; D000975:Antioxidants; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D043303:Aryldialkylphosphatase; D019610:Cytoprotection; D004950:Esterases / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis
D000975:Antioxidants; D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human