High levels of human apolipoprotein A-I and high density lipoproteins in transgenic mice do not enhance efflux of cholesterol from a depot of injected lipoproteins - Relevance to regression of atherosclerosis?

The role of high density lipoprotein (HDL) and apolipoprotein A-I (apo A-l) in promoting cholesterol efflux from cultured cells and attenuation of deve lopment of atherosclerosis in transgenic (tg) animals has been well documen ted. The aim of the present study was to determine whether high levels of h uman (h) apo A-I will enhance cholesterol removal in vivo, h apo A-I in ser a of tg mice was 429 +/- 18 and 308 +/- 10 mg/dl in male and female mice, t he ratio of phospholipid (PL) to apo A-I was 0.94 in tg and 2.4 and 1.9 in male and female controls, taking mouse apo A-I as 100 mg/dl. The removal of lipoprotein cholesterol injected in the form of cationized low density lip oprotein (cat-LDL) into the rectus femoris muscle of h apo A-I tg is compar ed with control mice. After injection of cat-LDL labeled with [H-3]choleste rol, the labeled cholesterol was cleared from the depot with a t1/2 of abou t 4 days in both control and tg mice. The clearance of the exogenous choles terol mass was initially much slower, it approached the t1/2 of about 4 day s between day 8 and 14 but there was no difference between tg and control m ice. Cholesterol efflux from cultured macrophages exposed to media containi ng up to 10% serum was 56% higher with serum from tg mice than controls. In conclusion, the efflux of cholesterol from a localized depot of cat-LDL wa s not enhanced in h apo A-I tg mice. It appears, therefore, that while an i ncrease above physiological levels of apo A-I or plasma HDL does play a piv otal role in the prevention of initiation and progression of early stages o f atherosclerosis, the effectiveness of such an increase for the I-egressio n stage remains still to be demonstrated. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.