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J Biol Chem, Vol. 273, Issue 9, 5033-5036, February 27, 1998
From the Department of Bioclimatology and Medicine, Medical
Institute of Bioregulation, Kyushu University, 4546 Tsurumihara,
Beppu, Oita 874, Japan and § Japan Tobacco Inc. Central
Pharmaceutical Research Institute, 1-1 Murasaki-cho,
Takatsuki, Osaka, 569-11 Japan
Cholesteryl ester transfer protein (CETP) is the
enzyme that facilitates the transfer of cholesteryl ester from high
density lipoprotein (HDL) to apolipoprotein B (apoB)-containing
lipoproteins. However, the exact role of CETP in the development of
atherosclerosis has not been determined. In the present study, we
examined the effect of the suppression of increased plasma CETP by
intravenous injection with antisense oligodeoxynucleotides (ODNs)
against CETP targeted to the liver on the development of
atherosclerosis in rabbits fed a cholesterol diet. The ODNs against
rabbit CETP were coupled to asialoglycoprotein (ASOR) carrier
molecules, which serve as an important method to regulate liver gene
expression. Twenty-two male Japanese White rabbits were used in the
experiment. Eighteen animals were fed a standard rabbit chow
supplemented with 0.3% cholesterol throughout the experiment for 16 weeks. At 8 weeks, they were divided into three groups (six animals in each group), among which the plasma total and HDL cholesterol concentrations did not significantly change. The control group received
nothing, the sense group were injected with the sense ODNs complex, and
the antisense group were injected with the antisense ODNs
complex, respectively, for subsequent 8 weeks.
ASOR·poly(L-lysine) ODNs complex were injected via
the ear veins twice a week. Four animals were fed a standard rabbit
diet for 16 weeks. The total cholesterol concentrations and the CETP
mass in the animals injected with antisense ODNs were all significantly
decreased in 12 and 16 weeks compared with those injected with sense
ODNs and the control animals. The HDL cholesterol concentrations
measured by the precipitation assay did not significantly change among
the groups fed a cholesterol diet, and triglyceride concentrations did
not significantly change in the four groups. However, at the end of the
study, when the HDL cholesterol concentrations were measured after the
isolation by ultracentrifugation and a column chromotography, they were
significantly higher in the animals injected with antisense ODNs than
in the animals injected with sense ODNs and in the control animals. A
reduction of CETP mRNA and an increase of LDL receptor mRNA in
the liver were observed in the animals injected with antisense ODNs
compared with those injected with sense ODNs and the control animals.
Aortic cholesterol contents and the aortic percentage lesion to total
surface area were significantly lower in the animals injected with
antisense ODNs than in the animals injected with sense ODNs and in the
control animals. These findings showed for the first time that
suppression of increased plasma CETP by the injection with antisense
ODNs against CETP coupled to ASOR carrier molecules targeted to the liver could thus inhibit the atherosclerosis possibly by decreasing the
plasma LDL + very low density lipoprotein (VLDL) cholesterol in
cholesterol-fed rabbits.
Effect of Antisense Oligonucleotides against Cholesteryl Ester
Transfer Protein on the Development of Atherosclerosis in
Cholesterol-fed Rabbits
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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