Effects of Mitogen-Activated Protein Kinase Pathway and Co-Activator CREP-Binding Protein on Peroxisome Proliferator-Activated Receptor-γ-Mediated Transcription Suppression of Angiotensin II Type 1 Receptor Gene

Abstract

Peroxisome proliferator-activated receptor (PPAR)-γ and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-γ 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-γ function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-γ 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-γ-mediated AT1R gene transcription suppression. We observed that 1) PPAR-γ-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-γ-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-γ-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-γ phosphorylation by the MAP kinase pathway may attenuate PPAR-γ-mediated AT1R gene transcription suppression through the inhibition of PPAR-γactivity; 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-γ-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-γ in AT1R gene transcription, probably leading to the progression of atherosclerosis. (Hypertens Res 2003; 26: 623-628)