Fruchart J C, Duriez P
Département d'Athérosclérose-INSERM U325, Institut Pasteur, Lille.
Bull Acad Natl Med. 1998;182(2):233-47; discussion 247-9.
Atherosclerosis is the leading cause of death in industrial societies. In France, 215 men out of 100,000 aged from 25 to 64 years old suffered of a myocardial infarction in 1992 and due to this disease 67 men out of 100,000 died. Hypercholesterolemia corresponding to a high LDL cholesterol level is an important risk factor of myocardial infarction. Nevertheless a low cholesterol level in the HDL fraction (frequently associated with an increase in triglycerides concentrations) is a common abnormality found in patients with confirmed coronary artery disease. Therefore, besides tentatives to reduce triglycerides and LDL cholesterol levels, a therapeutical strategy consists in increasing the serum HDL cholesterol concentration in order to improve the "reverse cholesterol transport". Apo A-I is the major protein of HDL. Studies in mice and rabbits transgenic for human apo A-I showed that overexpression of this protein in these animals resulted in an increase in the HDL cholesterol level. The serum of these animals contents a high concentration of particles containing human apo A-I but not mouse apo A-II (LpA-I) and presents a higher ability to induce cellular cholesterol efflux than the serum of the control mice. These alterations result in a reduction of atherosclerosis development when these animals are submitted to a cholesterol rich diet. Lecithin cholesterol acyl-transferase (LCAT) is a major enzyme in the metabolic cascade leading to the return of cholesterol to the liver. The metabolic role of LCAT is to esterify the free cholesterol of native HDL. Native HDL acquire free cholesterol during the transfer of cholesterol from the cell membrane to the particle during the cellular cholesterol efflux, which is the first step of the "reverse cholesterol transport". Mice and rabbits transgenic for human LCAT have higher HDL-cholesterol levels. Transgenic rabbits but not transgenic mice are protected against diet induced atherosclerosis development. Nevertheless, cholesterol fed mice which are transgenic for both human LCAT and simian cholesteryl ester transfer (CETP) protein do not develop atherosclerosis. This data indicates that over production of LCAT reduces atherosclerosis when CETP is naturally (rabbit) or artificially (CETP transgenic mice) expressed in the animals. Tentatives of gene therapy in mice induced by adenovirus-mediated transfer of human apo A-I and LCAT genes also increased circulating apo A-I and LCAT. Therefore apo A-I and LCAT are two potential targets for gene therapy in patients with atherosclerosis associated with a low HDL cholesterol level.
动脉粥样硬化是工业化社会中主要的死亡原因。在法国，1992年每10万名25至64岁的男性中有215人患心肌梗死，其中每10万人中有67人死于该病。高胆固醇血症对应着高LDL胆固醇水平，是心肌梗死的一个重要危险因素。然而，HDL部分胆固醇水平低（常与甘油三酯浓度升高相关）是确诊为冠状动脉疾病患者中常见的异常情况。因此，除了尝试降低甘油三酯和LDL胆固醇水平外，一种治疗策略是提高血清HDL胆固醇浓度以改善“胆固醇逆向转运”。载脂蛋白A-I是HDL的主要蛋白质。对转人类载脂蛋白A-I基因的小鼠和兔子的研究表明，该蛋白质在这些动物中的过表达导致HDL胆固醇水平升高。这些动物的血清中含有高浓度的含人类载脂蛋白A-I但不含小鼠载脂蛋白A-II的颗粒（LpA-I），并且与对照小鼠的血清相比，具有更高的诱导细胞胆固醇流出的能力。当这些动物食用富含胆固醇的饮食时，这些改变会导致动脉粥样硬化发展减缓。卵磷脂胆固醇酰基转移酶（LCAT）是导致胆固醇返回肝脏的代谢级联反应中的一种主要酶。LCAT的代谢作用是将天然HDL中的游离胆固醇酯化。在细胞胆固醇流出过程中，当胆固醇从细胞膜转移到颗粒时，天然HDL会获得游离胆固醇，这是“胆固醇逆向转运”的第一步。转人类LCAT基因的小鼠和兔子具有更高的HDL胆固醇水平。转基因兔子而非转基因小鼠可免受饮食诱导的动脉粥样硬化发展。然而，同时转人类LCAT和猿猴胆固醇酯转移蛋白（CETP）基因的喂食胆固醇的小鼠不会发生动脉粥样硬化。该数据表明，当CETP在动物中自然表达（兔子）或人工表达（CETP转基因小鼠）时，LCAT的过量产生可减轻动脉粥样硬化。由腺病毒介导的人类载脂蛋白A-I和LCAT基因转移诱导的小鼠基因治疗尝试也增加了循环中的载脂蛋白A-I和LCAT。因此，载脂蛋白A-I和LCAT是HDL胆固醇水平低的动脉粥样硬化患者基因治疗的两个潜在靶点。
