OVEREXPRESSION OF HUMAN LECITHIN CHOLESTERYL ACYLTRANSFERASE IN TRANSGENIC MICE

转基因小鼠中人卵磷脂胆固醇酰基转移酶的过度表达

• 批准号: 2576779
• 负责人: S SANTAMARINA-FOJO
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2576779
• 关键词: Adenoviridae; atherosclerosis; blood lipoprotein metabolism; cholesterol; enzyme activity; gene expression; genetically modified animals; hepatic lipase; high density lipoproteins; laboratory mouse; phosphatidylcholine sterol acyltransferase; transfection

Despite increased plasma concentrations of HDL, as well as apoA-I, LCAT transgenic (L-tg) mice have enhanced (up to 5-fold) diet induced atherosclerosis compared to age and sex matched controls. To investigate potential mechanisms that may explain this paradoxical dissociation between plasma concentrations of HDL and atherosclerosis we have used recombinant adenovirus vectors to express, in vivo, two other proteins that play a major role in HDL metabolism. Adenovirus-mediated expression of HL and CETP in both control and L-tg mice demonstrated that compared to the HDL in control animals, the apoA-I/A-II HDL in L-tg mice were poorly hydrolyzed by HL and would not support the transport of cholesteryl esters to apoB containing lipoproteins by CETP. Additionally, baseline plasma concentrations of nascent, pre-B1-HDL, the most effector particles for the efflux of cellular cholesterol, were significantly reduced in L-tg mice. The decay plasma curve of L-tg mouse HDL after injection of radiolabelled HDL-cholesterol ether isolated from control and L-tg mice was significantly delayed from that of control mouse HDL. In addition, the % of total cholesterol ether delivered to the liver, two hours after injection of radiolabelled HDL, was significantly reduced (P<0.001) for L-tg mice compared to controls (18% versus 33% of total cholesterol ether). These combined studies indicate that in the absence of CETP, LCAT overexpression in mice leads to the formation of HDL particles with abnormal composition and function, establishing one potential mechanism that may account for the enhanced atherosclerosis observed in this animal model. Thus, the process of reverse cholesterol transport, an important mechanism by which HDL may modulate the development of atherosclerosis is interrupted in L-tg mice. These studies demonstrate that HDL and apoA-I plasma concentrations, alone, are not predictive of the anti-atherogenic potential of HDL and functional studies are required to determine whether increasing plasma HDL by different therapeutic modalities will if fact, protect against the development of premature cardiovascular disease.

尽管血浆HDL浓度增加，以及apoA-I，LCAT 转基因（L-tg）小鼠具有增强的（高达5倍）饮食诱导的 与年龄和性别匹配的对照组相比，动脉粥样硬化。 探讨 可能解释这种矛盾分离的潜在机制 血浆高密度脂蛋白浓度和动脉粥样硬化之间的关系 重组腺病毒载体以在体内表达两种其它蛋白质 在高密度脂蛋白代谢中起主要作用。腺病毒介导表达 HL和CETP在对照组和L-tg小鼠中的表达表明， 与对照动物的HDL相比，L-tg小鼠的apoA-I/A-II HDL HL水解不良，不支持转运 胆固醇酯与含载脂蛋白B的脂蛋白。此外，本发明还 基线血浆浓度的新生，前B1-HDL，最效应 细胞胆固醇流出的颗粒，显着 在L-tg小鼠中降低。L-tg小鼠HDL的血浆衰减曲线 注射从对照品中分离的放射性标记HDL-胆固醇醚 而L-tg小鼠的HDL表达明显延迟于对照小鼠。 此外，传递到肝脏的总胆固醇醚的%， 在注射放射性标记的HDL后24小时， L-tg小鼠与对照组相比（18%对33%）（P<0.001） 胆固醇醚）。 这些综合研究表明，在没有CETP，LCAT 在小鼠中的过度表达导致HDL颗粒的形成， 异常的组成和功能，建立一个潜在的机制， 这可以解释在这只动物中观察到的动脉粥样硬化增强 模型 因此，胆固醇的逆向转运过程， HDL调节动脉粥样硬化发展的机制 在L-tg小鼠中被中断。这些研究表明，HDL和 apoA-I血浆浓度本身并不能预测 需要HDL的抗动脉粥样硬化潜力和功能研究， 确定不同治疗方法是否会增加血浆HDL 如果事实上，模式将防止不成熟的发展， 心血管疾病