Effects of mitogen-activated protein kinase pathway and co-activator CREP-binding protein on peroxisome proliferator-activated receptor-gamma-mediated transcription suppression of angiotensin II type 1 receptor gene.
Peroxisome proliferator-activated receptor (PPAR)-gamma and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the --58/--34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-gamma function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-gamma and modulates its activity. Since both the MAP kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-gamma-mediated AT1R gene transcription suppression. We observed that 1) PPAR-gamma-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect; 2) the PPAR-gamma-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-gamma-mediated AT1R gene transcription suppression; and 4) the CBP effect was eliminated when the --58/--34 GC-box related element was disrupted. It is therefore speculated that: 1) PPAR-gamma phosphorylation by the MAP kinase pathway may attenuate PPAR-gamma-mediated AT1R gene transcription suppression through the inhibition of PPAR-gamma activity; and 2) CBP may enhance the activity of the remaining Sp1 on the --58/--34 GC-box related element, resulting in a reduction in PPAR-gamma-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-gamma in AT1R gene transcription, probably leading to the progression of atherosclerosis.
Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. akiras@mail.cc.tohoku.ac.jp
Akira
A
Sugawara
Kazuhisa
K
Takeuchi
Akira
A
Uruno
Masataka
M
Kudo
Kazunori
K
Sato
Sadayoshi
S
Ito
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology; D050882:CREB-Binding Protein; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013489:Suppression, Genetic / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D009687:Nuclear Proteins; D044140:Receptor, Angiotensin, Type 1; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one