Lovastatin decreases the receptor-mediated degradation of acetylated and oxidized LDLs in human blood monocytes during the early stage of differentiation into macrophages
N. Hrboticky et al., Lovastatin decreases the receptor-mediated degradation of acetylated and oxidized LDLs in human blood monocytes during the early stage of differentiation into macrophages, ART THROM V, 19(5), 1999, pp. 1267-1275
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are used therape
utically to upregulate the LDL receptor-mediated removal of plasma choleste
rol by the liver. Several lines of evidence indicate that these drugs also
exert direct effects on the metabolism of native and modified LDL in extrah
epatic cells. We studied the effects of lovastatin (LOV) on the degradation
of native, acetylated, and oxidized LDL, and on levels of mRNA encoding fo
r the LDL, types I and TT class A macrophage scavenger, and CD36 receptors
in human blood monocytes at different stages of their maturation into adher
ent macrophages. LOV (10 mu mol/L) reduced the degradation of acetylated LD
L when added to freshly isolated cells cultured for 2 (81+/-4% of control,
P<0.05) and 5 (76+/-6%, of control, P<0.05) days. The degradation of oxidiz
ed LDL was also reduced in cells treated with LOV for 2 days after seeding
(51+/-3% of control, P<0.001) but not in 5-day-old cells. LOV had no signif
icant effect on the degradation of either acetylated or oxidized LDL when a
dded to fully matured macrophages allowed to differentiate under control co
nditions for 7 days before incubations with 10 mu mol/L LOV for an addition
al 2 days. In contrast, LOV increased the degradation of native LDL in thes
e cells at all 3 stages of cell differentiation. LOV also reduced class A t
ypes I and II macrophage scavenger receptor and CD36 mRNA levels in 2- and
5-day-old cells but not in the more mature macrophages. These data suggest
that 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors may reduce the expres
sion and function of the class A types I and II macrophage scavenger recept
or and CD36 in monocytes, during the early stages of their differentiation
into adherent macrophages. These effects, if operative in vivo, may slow do
wn the development of the atherosclerotic plaque and thus contribute to the
beneficial effects of these drugs.