Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-induced macrophage proliferation.
Macrophage-derived foam cells play important roles in the progression of atherosclerosis. We reported previously that ERK1/2-dependent granulocyte/macrophage colony-stimulating factor (GM-CSF) expression, leading to p38 MAPK/ Akt signaling, is important for oxidized low density lipoprotein (Ox-LDL)-induced macrophage proliferation. Here, we investigated whether activation of AMP-activated protein kinase (AMPK) could suppress macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages was assessed by [(3)H]thymidine incorporation and cell counting assays. The proliferation was significantly inhibited by the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and restored by dominant-negative AMPKalpha1, suggesting that AMPK activation suppressed macrophage proliferation. AICAR partially suppressed Ox-LDL-induced ERK1/2 phosphorylation and GM-CSF expression, suggesting that another mechanism is also involved in the AICAR-mediated suppression of macrophage proliferation. AICAR suppressed GM-CSF-induced macrophage proliferation without suppressing p38 MAPK/Akt signaling. GM-CSF suppressed p53 phosphorylation and expression and induced Rb phosphorylation. Overexpression of p53 or p27(kip) suppressed GM-CSF-induced macrophage proliferation. AICAR induced cell cycle arrest, increased p53 phosphorylation and expression, and suppressed GM-CSF-induced Rb phosphorylation via AMPK activation. Moreover, AICAR induced p21(cip) and p27(kip) expression via AMPK activation, and small interfering RNA (siRNA) of p21(cip) and p27(kip) restored AICAR-mediated suppression of macrophage proliferation. In conclusion, AMPK activation suppressed Ox-LDL-induced macrophage proliferation by suppressing GM-CSF expression and inducing cell cycle arrest. These effects of AMPK activation may represent therapeutic targets for atherosclerosis.
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
Norio
N
Ishii
Takeshi
T
Matsumura
Hiroyuki
H
Kinoshita
Hiroyuki
H
Motoshima
Kanou
K
Kojima
Atsuyuki
A
Tsutsumi
Shuji
S
Kawasaki
Miyuki
M
Yano
Takafumi
T
Senokuchi
Tomoichiro
T
Asano
Takeshi
T
Nishikawa
Eiichi
E
Araki
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008077:Lipoproteins, LDL; D012265:Ribonucleotides; C099252:oxidized low density lipoprotein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000620:Aminoimidazole Carboxamide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide