ATHEROGENESIS IN TRANSGENIC MICE WITH HUMAN APOLIPOPROTEIN-B AND LIPOPROTEIN (A)

The engineering of mice that express a human apoB transgene has result ed in animals with high levels of humanlike LDL particles and through crosses with human apo(a) transgenics, high levels of human-like lipop rotein (a) (Lp[a]) particles, In this study, these animals have been u sed to compare the atherogenic properties of apo(a), LDL, and Lp(a), T he presence of the high expressing apoB (apoBH) transgene was associat ed with a 2.5-fold increase in VLDL-LDL cholesterol (primarily in the LDL fraction) and a 15-fold increase in proximal lesions compared with non-transgenic mice (P less than or equal to 0.0001), while the prese nce of the low expressing human apoB (apoBL) transgene was not associa ted with major changes in lipoprotein profiles or increases in aortic lesion size, Examination of aortas of apoBH mice demonstrated lesions along the entire length of the aorta and immunochemical analysis of th e lesions revealed features characteristically seen in human lesions i ncluding the presence of oxidized lipoproteins, macrophages, and immun oglobulins. Unlike animals with the apoBL transgene, animals with the apo(a) transgene had significant increases in proximal aortic fatty st reak lesions compared to nontransgenic control animals (threefold; P < 0.02), while animals with both transgenes, the apo(a)/apoBL double tr ansgenics, had lesions 2.5 times greater than animals expressing the a po(a) transgene alone and eightfold (P < 0.0006) greater than nontrans genic animals, These murine studies demonstrate that marked increases in apoB and LDL resulted in atherosclerotic lesions extending down the aorta which resemble human lesions immunochemically and suggest that apo(a) associated with apoB and lipid may result in a more pro-atherog enic state than when apo(a) is free in plasma.