PPARgamma phosphorylation mediated by JNK MAPK: a potential role in macrophage-derived foam cell formation.
OBJECTIVE
To investigate whether oxidized low-density lipoprotein (ox-LDL) modulates peroxisome proliferator-activated receptor gamma (PPARgamma) activity through phosphorylation in macrophages, and the effect of PPARgamma phosphorylation on macrophages-derived foam cell formation.


METHODS
After exposing the cultured THP-1 cells to ox-LDL in the presence or absence of different mitogen-activated protein kinase (MAPK) inhibitors, PPARgamma and phosphorylated PPARgamma protein levels were detected by Western blot. MAPK activity was analyzed using MAP Kinase Assay Kit. Intracellular cholesterol accumulation was assessed by Oil red O staining and cholesterol oxidase enzymatic method. The mRNA level of PPARgamma target gene was determined by reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
ox-LDL evaluated PPARgamma phosphorylation status and subsequently decreased PPAR gamma target gene expression in a dose-dependent manner. ox-LDL also induced MAPK activation. Treatment of THP-1 cells with c-Jun N-terminal kinase-, but not p38- or extracellular signal-regulated kinase-MAPK inhibitor, significantly suppressed PPARgamma phosphorylation induced by ox-LDL, which in turn inhibited foam cell formation.


CONCLUSIONS
In addition to its ligand-dependent activation, ox-LDL modulates PPAR gamma activity through phosphorylation, which is mediated by MAPK activation. PPARgamma phosphorylation mediated by MAPK facilitates foam cell formation from macrophages exposed to ox-LDL.
Yin
Ran
R
Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Dong
Yu-gang
YG
Li
Hong-liang
HL
D000873:Anthracenes / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000873:Anthracenes; D007093:Imidazoles; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D011725:Pyridines; C099252:oxidized low density lipoprotein; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580