Oxidized low density lipoprotein inhibits macrophage apoptosis through activation of the PI 3-kinase/PKB pathway

Citation
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
Citations number
54
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF LIPID RESEARCH
ISSN journal
00222275 → ACNP
Volume
42
Issue
9
Year of publication
2001
Pages
1483 - 1491
Database
ISI
SICI code
0022-2275(200109)42:9<1483:OLDLIM>2.0.ZU;2-O
Abstract
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.