[Reverse cholesterol transport and use of transgenic mice and rabbits to reveal candidate genes for protection against atherosclerosis].

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.