INHIBITION OF DIET-INDUCED ATHEROMA FORMATION IN TRANSGENIC MICE EXPRESSING APOLIPOPROTEIN-E IN THE ARTERIAL-WALL

Apolipoprotein E (apoE) plays a crucial role in lipoprotein metabolism both in plasma and in peripheral tissues. To test whether apoE in the vascular wall has a direct and local effect on atherogenesis, we esta blished transgenic mice expressing human apoE under control of H2 Ld p romoter. Studies on mRNA levels and immunohistochemistry demonstrated that this line was characterized by high expression of human apoE in t he arterial wall while its expression was relatively low in other tiss ues as compared with the respective endogenous expression of mouse apo E. They showed no difference in plasma cholesterol levels and lipoprot ein profile from controls when fed both normal and atherogenic diets. However, after 24 wk of an atherogenic diet, the formation of fatty st reak lesions in proximal aorta was markedly inhibited in transgenic mi ce as compared with controls. Both lesion area and esterified choleste rol content were < 30% of those in controls. In a tissue cholesterol l abeling study with H-3-cholesterol, the specific activity of aorta cho lesterol was much less in transgenic mice, suggesting that apoE enhanc es cholesterol efflux from the aortic wall into plasma. Thus, apoE has anti-atherogenic action which is mediated via enhancing reverse chole sterol transport from arterial wall.