Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL.
Endocytosis of oxidized low density lipoproteins (oxLDL) by macrophages, mediated by scavenger receptors, is thought to play a central role in foam cell formation and, thus, in the pathogenesis of atherosclerosis. OxLDL activates several MAP kinases, including the ERK, JNK and p38 MAP kinases, but the role of these activations in oxLDL uptake has not been studied. In the present investigation, we find that SB203580, a specific inhibitor of p38, blocks oxLDL-exposed J774 cells from becoming foam cells. Inhibition of foam cell formation by blockade of the p38 pathway is, at least in part, due to inhibition of oxLDL-induced up-regulation of the scavenger receptor CD36. Using pharmaceutical inhibitors and dominant active MAP kinase kinases, we demonstrated that activation of the p38 pathway, but not the ERK or JNK pathways, is necessary and sufficient to transactivate PPARgamma, a nuclear receptor that has recently been shown to play a pivotal role in oxLDL-induced CD36 expression. Our results for the first time demonstrate a regulation of CD36 by p38, and the importance of the p38 pathway in regulation of foam cell formation.
Division of Pathology II, Faculty of Health Sciences, Linköping University, Sweden. ming.zhao@inr.liu.se
Ming
M
Zhao
Yawei
Y
Liu
Xiaofei
X
Wang
Liguo
L
New
Jiahuai
J
Han
Ulf T
UT
Brunk
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D004789:Enzyme Activation; D005487:Foam Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D018955:CD36 Antigens; D007093:Imidazoles; D008077:Lipoproteins, LDL; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580