HUMAN APOLIPOPROTEIN A-II IS A PRO-ATHEROGENIC MOLECULE WHEN IT IS EXPRESSED IN TRANSGENIC MICE AT A LEVEL SIMILAR TO THAT IN HUMANS - EVIDENCE OF A POTENTIALLY RELEVANT SPECIES-SPECIFIC INTERACTION WITH DIET

We report on the effect of human apolipoprotein (ape) A-II transgene e xpression on atherosclerosis susceptibility in two transgenic lines (2 5.3 and 11.1) whose plasma human apoA-II concentrations (similar to 23 and 96 mg/dl, respectively) span the normal range in humans. After 9 months of an atherogenic diet, 25.3 and 11.1 transgenic mice developed aortic atherosclerotic lesions that were similar to 1.7- and 7-fold, respectively, more extensive than those of nontransgenic control mice. However, there was no difference in the area of atherosclerosis of tr ansgenic and control mice when fed a regular chow diet. This contrasts with the findings in murine apoA-II transgenic mice and provides evid ence of a species-specific characteristic that could be of relevance w ith respect to the high fat intake diets common in most industrialized countries. A possible mechanism of the pro-atherogenic action of huma n apoA-II could be the inhibition of reverse cholesterol transport and , in support of this, we observed an impairment of apoA-I-HDL particle interconversion in the plasma of 11.1 transgenic mice caused, at leas t in part, by a marked decrease in the endogenous lecithin:cholesterol acyltransferase activity.