SUBSTITUTION OF THE CARBOXYL-TERMINAL DOMAIN OF APO AI WITH APO AII SEQUENCES RESTORES THE POTENTIAL OF HDL TO REDUCE THE PROGRESSION OF ATHEROSCLEROSIS IN APO-E KNOCKOUT MICE

HDL metabolism and atherosclerosis were studied in apo E knockout (KO) mice overexpressing human apo AT, a des(190-243)-apo AT carboxyl-term inal deletion mutant of human apo AI or an apo AI-(1-189)-apo AII-(12- 77) chimera in which the carboxyl-terminal domain of apo AT was substi tuted with the pair of helices of apo ATI. HDL cholesterol levels rank ed: apo AI/apo E KO similar to apo AI-(1-189)-apo ATT(12-77)/apo E KO > > des-(190-243)-apo AI/apo E KO > apo E KO mice. Progression of athe rosclerosis ranked: apo E KO > des-(190-243)-apo AI/apo E KO > > apo A I-(1-189)apo AII-(12-77)/apo E KO similar to apo AI/apo E KO mice. Whe reas the total capacity to induce cholesterol efflux from lipid-loaded THP-1 macrophages was higher for HDL of mice overexpressing human apo AI or the apo AI/apo AIT chimera, the fractional cholesterol efflux r ate, expressed in percent cholesterol efflux/mu g apolipoprotein/h, fo r HDL of these mice was similar to that for HDL of mice overexpressing the deletion mutant and for HDL of apo E KO mice. This study demonstr ates that the tertiary structure of apo AT, e.g., the number and organ ization of its helices, and not its amino sequence is essential for pr otection against atherosclerosis because it determines HDL cholesterol levels and not cholesterol efflux. Amino acid sequences of apo AII, w hich is considered to be less antiatherogenic, can be used to restore the structure of apo AT and thereby its antiathero-genicity.