Functional Validation of Transgenes for the Development of a Transgenic Hypertensive Rat Atherosclerosis Model

Abstract

We have utilized the Dahl-S hypertensive rat in order to develop transgenic rat lines carrying the human cholesteryl ester transfer protein (CETP) gene. The overexpression of the CETP gene, and the hypertensive genetic background of the Dahl-S rat are expected to accelerate the development of atherosclerosis in response to high salt high cholesterol diet, thus providing an animal model of atherosclerosis that would resemble human atherosclerotic lesions. CETP is a component of the reverse cholesterol transport pathway, and it may play a proatherogenic role (1). This is consistent with the observed lipoprotein profile changes in studies of CETP deficiency or overexpression, including: (a) human subjects deficient in CETP (2); (b) overexpression of the human (3) or simian (4) CETP gene in transgenic mice; (c) infusion of CETP into rats (5); (d) the in vivo inhibition of CETP in rabbits (6) and hamsters (7) using CETP neutralizing monoclonal antibodies. In addition, species which have relatively high levels of plasma CETP activity (e.g. human, monkey, rabbit) are susceptible to atherosclerosis, whereas species with low or absent CETP activity (e.g. dog, rat, mouse) are relafively resistant to atherosclerosis (8). Pigs are an exception since they lack CETP activity but present atheroma with diet-induced hyper-cholesterolemia. Moreover, CETP plasma concentrations are directly associated with intima media thickening of carotid arteries (9). However, to date the beneficial or detrimental effects of CETP on atherosclerosis remain to be conclusively established (1), and conflicting observations (10, 11) emphasize the need for further study of the relationship between CETP and development of atherosclerosis.