Increased levels of high-density lipoprotein cholesterol are ineffective in inhibiting the development of immune responses to oxidized low-density lipoprotein and atherosclerosis in transgenic rabbits expressing human apolipoprotein (apo) A-1 with severe hypercholesterolaemia

High levels of high-density lipoprotein (HDL) cholesterol have been reporte d to protect against the development of atherosclerosis in humans by increa sing reverse cholesterol transport and inhibiting the oxidation of low-dens ity lipoprotein (LDL) due to the paraoxonase content of HDL. The purpose of the present study was to assess if there are any relationships between in vivo increases in serum levels of immunological LDL oxidation markers [auto antibodies against oxidized LDL, autoantibodies against malondialdehyde-mod ified LDL, LDL immune complexes and anti-cardiolipin autoantibodies], parao xonase activity and the development of atherosclerosis in control rabbits a nd in transgenic rabbits expressing human apolipoprotein (apo) A-I. A total of 13 apo A-I transgenic rabbits and 18 non-transgenic littermates were fe d on a cholesterol-rich diet (0.4%, w/w) for 14 weeks, and were monitored a t weeks 0, 2, 6, 10 and 14. Aortic atherosclerotic lesions were measured at the end of this period. Human apo A-I transgenic rabbits with high HDL cho lesterol levels were not protected against the development of atheroscleros is when they were fed on a cholesterol-rich diet which induced dramatic hyp ercholesterolaemia. Immunological markers of LDL oxidation increased and se rum paraoxonase activity decreased similarly in control and transgenic rabb its. In conclusion, the present study demonstrates that high HDL cholestero l levels are ineffective in inhibiting increases in immunological markers o f LDL oxidation acid the development of atherosclerosis in a mammal with se vere hypercholesterclaemia.