Rs. Hundal et al., Oxidized low density lipoprotein inhibits macrophage apoptosis through activation of the PI 3-kinase/PKB pathway, J LIPID RES, 42(9), 2001, pp. 1483-1491
Oxidized LDL (oxLDL) is known to induce endothelial adhesion molecule and m
onocyte chemoattractant protein I expression and this is thought to be invo
lved in monocyte recruitment into atherosclerotic lesions. oxLDL has also b
een found to induce macrophage proliferation. The purpose of the present st
udy was to determine whether oxLDL might also have the ability to increase
macrophage populations by inhibiting apoptosis. We found that oxLDL caused
a dose-dependent inhibition of the apoptosis that occurs in cultured bone m
arrow-derived macrophages after macrophage colony-stimulating factor (M-CSF
) withdrawal without inducing proliferation. Incubation of macrophages with
either native LDL or acetylated LDL had no effect on apoptosis. The prosur
vival effect of oxLDL was not inhibited by neutralizing antibodies to granu
locyte-macrophage colony-stimulating factor, was maintained in mice homozyg
ous for a mutation in the M-CSF gene, and was not due to other secreted cyt
okines or growth factors. oxLDL caused activation of the mitogen-activated
protein kinases ERK1/2 (extracellular signal-regulated kinases 1 and 2) as
well as protein kinase B (PKB), a target of phosphatidylinositol 3-kinase (
PI 3-kinase). Furthermore, there was phosphorylation of two important prosu
rvival PKB targets, I-kappaB alpha (Ser-32) and Bad(Ser-136). The MEK inhib
itors PD 98059 and U0126 blocked ERK1/2 activation but did not diminish sur
vival. Conversely, the PI 3-kinase inhibitors LY 294002 and wortmannin bloc
ked PKB activation, and the ability of oxidized LDL to promote macrophage s
urvival. Taken together, these results indicate that oxLDL can directly act
ivate a PI 3-kinase/PKB-dependent pathway that permits macrophage survival
in the absence of growth factors.