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
P. Holvoet et al., 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, The Journal of clinical investigation, 102(2), 1998, pp. 379-385
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.