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

胆固醇酯转运蛋白（CETP）反义寡脱氧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CETP反义寡脱氧核苷酸（ODNs），观察其对高脂饮食兔动脉粥样硬化形成的影响。ASOR-聚（L）赖氨酸-ODNs复合物经耳静脉注射，每周2次。与正义ODNs组和对照组相比，注射反义ODNs组动物的总胆固醇浓度和CETP质量在12周和16周均显著降低。当通过超离心和柱色谱分离后测量HDL胆固醇浓度时，注射反义ODNs的动物中的HDL胆固醇浓度显著高于注射有义ODNs的动物和对照动物。一种还原剂 ...更多信息 与正义ODNs组和对照组相比，反义ODNs组肝组织中CETP mRNA水平明显升高，LDL-R mRNA水平明显升高。在Hep G2细胞中，前β HDL的分泌随着胆固醇酯转运蛋白的抑制而增加。在本研究中，我们检测了反义寡脱氧核苷酸（ODNs）对肝CETP的抑制作用。用Hep G2细胞培养物对抗CETP靶向肝脏对apo A-I分泌的影响。对照组给予生理盐水，正义组与正义ODNs复合物混合，反义组与反义ODNs复合物混合，持续2d。反义组肝细胞CETP mRNA和培养基中CETP质量均显著低于正义组和对照组。反义组肝组织apoA-I mRNA表达和apoA-I质量均显著高于正义组和对照组。载脂蛋白A-1的增加主要是由于前β载脂蛋白A-1的增加。反义寡核苷酸降低血浆血管紧张素原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AGT的反义寡核苷酸（ODNs）抑制血浆AGT对自发性高血压大鼠（SHR）血管重构的影响。10周龄时，SHR分为3组（每组6只），其中收缩压（BP）无明显变化。对照组注射生理盐水，正义组注射正义ODNs复合物，反义组注射反义ODNs复合物。WKY大鼠喂食相同时间。ASOR-poly（L）lysine-ODNs复合物经尾静脉注射，每周2次。在治疗结束时，与SHR和WKY大鼠的其他组相比，仅在注射反义ODNs的动物中观察到肝脏和血浆AGT中AGT mRNA的减少。反义ODNs能显著降低WKY大鼠血浆血管紧张素II（AngII）浓度。反义ODNs可显著降低SHR血压和主动脉中膜横截面积，但仍大于对照组和正义ODNs注射组; SHR主动脉血管紧张素转换酶（ACE）活性和胶原含量无显著变化，但明显高于WKY组; SHR主动脉AGT、ACE、血管紧张素1型（AT 1）受体和血管紧张素2型（AT 2）受体mRNA在SHR各组间无明显变化。少

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