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

抗胆固醇酯转移蛋白的反义寡脱氧核苷酸对高胆固醇家兔动脉粥样硬化发展的影响在本研究中，我们研究了静脉注射抗肝脏CETP的反义寡脱氧核苷酸（ODNs）对高胆固醇家兔血浆CETP升高的抑制作用。每周2次经耳静脉注射ASOR-poly (L) lysine-ODNs cornplex。在12周和16周时，注射反义ODNs的动物总胆固醇浓度和CETP质量均明显低于注射正义ODNs的动物和对照组。分离后用超离心和柱层析法测定高密度脂蛋白胆固醇浓度，反义odn注射组明显高于义odn注射组和对照组。反义ODNs注射组与正常ODNs注射组及对照组相比，肝脏中CETP mRNA含量明显降低，LDL-R mRNA含量明显升高。反义ODNs注射组的主动脉胆固醇含量和主动脉病变占总表面积的百分比明显低于正义ODNs注射组和对照组。在hepg2细胞中，随着胆固醇酯转移蛋白的抑制，前β - HDL的分泌增加。在本研究中，我们利用hepg2细胞培养，研究了针对肝脏CETP的反义寡脱氧核苷酸（ODNs）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，正义组与正义ODNs复合物混合，反义组与反义ODNs复合物混合，疗程2 d。反义组肝脏CETP mRNA和培养液中CETP质量均显著低于正义组和对照组。反义组肝脏apo a - 1 mRNA和培养基中apo a - 1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β前期载脂蛋白a - 1的增加。反义寡脱氧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在本研究中，我们观察了静脉注射抗AGT的反义寡脱氧核苷酸（ODNs）抑制血浆AGT对自发性高血压大鼠血管重构的影响。10周龄时，将SHR分为3组（每组6只），各组收缩压（BP）无明显变化。10 ~ 20周龄，对照组给予生理盐水，正组给予正ODNs复合物，反义组给予反义ODNs复合物。WKY大鼠同样喂养一段时间。通过尾静脉注射ASOR-poly(L)lysine-ODNs复合物，每周2次。在治疗结束时，与其他各组SHR和WKY大鼠相比，仅注射反义ODNs的动物肝脏和血浆AGT mRNA减少。反义ODNs可显著降低血浆血管紧张素II （Ang II）浓度至WKY大鼠水平。反义ODNs显著降低了大鼠的血压和主动脉介质横截面积，与注射感觉ODNs的SHR和对照SHR相比，仍比WKY大鼠大。大鼠主动脉血管紧张素转换酶（ACE）活性和胶原蛋白浓度显著高于WKY大鼠，但SHR各组间无显著变化。SHR组主动脉AGT、ACE、血管紧张素1型（AT1）受体和血管紧张素2型（AT2）受体mRNA均无显著变化。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