| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Effect of Antisense Oligodeoxynucleotides against Cholesteryl Ester Transfer Protein on the Development of Atherosclerosis in Cholesterol -fed Rabbits
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. ASOR-poly (L) lysine-ODNs cornplex were injected via The ear veins twice a week. 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. 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 reduct
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ion of CETP mRNA and an increase of LDL-R 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.
Secretion of prebeta HDL increases with the suppression of cholesteryl ester transfer protein in Hep G2 cells In the present stud we examined the effect of the suppression of hepatic CETP by antisense oligodeoxynucleotides (ODNs) against CETP targeted to the liver on the secretion of apo A-I using a Hep G2 cell culture. The control group received saline, while the sense group was mixed with the sense ODN s complex and the antisense group was mixed with the antisense ODNs complex, respectively, for 2 days. Both the hepatic CETP mRNA and the CETP mass in the medium in the antisense group decreased significantly more than in the sense and the control groups. In contrast, both the hepatic a p o A-I mRNA and the apo A-l mass in the medium in the antisense group were significantly higher than those in the sense and the control groups. The increase in apo A-l was mainly due to the increase in prebeta apo A-I.
Effects of Reduced Plasma Angiotensinogen by Antisense Oligodeoxynucleotides on Vascular Remodeling in Spontaneously Hypertensive Rats
In the present study, we examined the effect of the suppression of plasma AGT by intravenous injection with antisense oligodeoxynucleotides (ODNs) against AGT targeted to the liver on the vascular remodeling in spontaneously hypertensive rats ( SHR ). At 1 0 weeks of age, SHR were divided into 3 groups ( six animals in each group ), among which the systolic blood pressure (BP) did not significantly change. The control group received saline, the sense group were injected with the sense ODNs complex and the antisense group were injected with the antisense ODNs complex, respectively, from 10 to 20 weeks of age. WKY rats were fed for the same period of time. ASOR-poly(L)lysine-ODNs complex were injected via the tail veins twice a week. At the end of the treatment, a reduction of AGT mRNA in the liver and plasma AGT were observed only in the animals injected with antisense ODNs compared with the other groups of SHR and WKY rats. Antisense ODNs were found to have significantly reduced the plasma angiotensin II (Ang II) concentration to the level of WKY rats. Antisense ODNs significantly reduced BP and media cross-sectionaI area of the aorta, which were still larger than WKY rats, in comparison to the SHR injected with sense ODNs and control SHR.The aortic angiotensin converting enzyme (ACE) activity and collagen concentration, which was significantly higher than those in WKY rats, did not significantly change among the groups of SHR.The aortic AGT, ACE, angiotensin type 1 (AT1) receptor and angiotensin type 2(AT2) receptor mRNA did not significantly change either among the groups of SHR. Less
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