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Study for lipid metabolism and atherosclerosis using antisense oligodeoxy nucleotides targeted to liver

使用靶向肝脏的反义寡脱氧核苷酸研究脂质代谢和动脉粥样硬化

基本信息

批准号：
09670727
负责人：
SUGANO Masahiro
金额：
$ 2.05万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670727/
关键词：
Atherosclerosis Liver Antisense Oligodeoxynucleotides Prebeta HDL Angiotensininogen Asialoglycoprotein-poly (L) lysine : DNA complex Vascular remodeling Cholesteryl ester transfer protein アンチセンス

项目摘要

Effect of Antisense Oligodeoxynucleotides against Cholesteryl Ester Transfer Protein on the Development of Atherosclerosis in Cholesterol -fed RabbitsIn 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 … More 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 RatsIn 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

针对胆固醇酯转运蛋白的反义寡核苷酸对高脂饮食兔动脉粥样硬化形成的影响本研究通过静脉注射针对肝脏的针对CETP的反义寡核苷酸来抑制高脂饮食兔血浆CETP的升高，探讨其对高脂饮食兔动脉粥样硬化形成的影响。每周两次耳缘静脉注射ASOR-聚(L)赖氨酸-寡核苷酸复合体。在12周和16周，注射反义ODN的动物的总胆固醇浓度和CETP质量均显著低于注射正义ODN的动物和对照组。超速离心和柱层析分离后测定高密度脂蛋白胆固醇浓度时，注射反义寡核苷酸的动物的高密度脂蛋白浓度显著高于注射正义寡核苷酸的动物和对照组。A Reduct…注射反义ODN组大鼠肝脏CETP基因表达明显高于正义ODN组和对照组，肝组织低密度脂蛋白受体基因表达明显高于正义ODN组和对照组。注射反义ODN的动物的主动脉胆固醇含量和病变占总表面积的百分比明显低于注射正义ODN的动物和对照组动物。Hep G2细胞分泌前β-高密度脂蛋白随着胆固醇酯转运蛋白的抑制而增加。本研究采用Hep G2细胞培养方法，观察了针对CETP的反义寡核苷酸抑制肝脏CETP对载脂蛋白A-I分泌的影响。对照组给予生理盐水，正义组加入正义寡核苷酸S复合体，反义组加入反义寡核苷酸复合体，共2d。反义组大鼠肝脏CETP mRNA和培养液中CETP质量下降幅度均明显大于正义组和对照组。反义寡核苷酸组大鼠肝细胞膜载脂蛋白A-IMRNA和载脂蛋白A-L质量均显著高于正义组和对照组。载脂蛋白A-L的升高主要是由于载脂蛋白A-I的增加，反义寡核苷酸降低血浆血管紧张素原水平对自发性高血压大鼠血管重构的影响本研究观察了静脉注射针对肝组织血管紧张素原的反义寡核苷酸抑制自发性高血压大鼠血管重构的作用。10周龄时，SHR分为3组，每组6只，其中收缩压无明显变化。10~20周龄，对照组注射生理盐水，正义组注射正义寡核苷酸复合体，反义组注射反义寡核苷酸复合体。WKY大鼠饲喂相同时间。尾静脉注射ASOR-多(L)赖氨酸-寡核苷酸复合体，每周2次。治疗结束时，与SHR和WKY大鼠相比，仅注射反义ODN的大鼠肝组织AGT mRNA和血浆AGT表达下降。反义寡核苷酸显著降低血浆血管紧张素II(Ang II)浓度至WKY大鼠水平。与SHR组和对照SHR组相比，反义ODN显著降低了SHR大鼠的血压和主动脉中膜横截面积，但仍大于WKY大鼠。SHR组大鼠的主动脉血管紧张素转换酶(ACE)活性和胶原浓度显著高于WKY组大鼠，而血管紧张素转换酶(ACE)、血管紧张素转换酶(AT1)受体和血管紧张素受体2(AT2)受体的mRNA在SHR组之间也没有明显变化。较少