Platelet-derived growth factor promotes the expression of peroxisome proliferator-activated receptor γ in vascular smooth muscle cells by a phosphatidylinositol 3-kinase/Akt signaling pathway

Abstract

Vascular diseases such as atherosclerosis are characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs) within the intimal lining. The intimal VSMCs exhibit an increased expression of peroxisome proliferator-activated receptor γ (PPAR-γ), and the administration of pharmacological PPAR-γ agonists attenuates vascular lesion formation. The factors that regulate PPAR-γ expression in the vasculature are poorly defined. Here we report that platelet-derived growth factor (PDGF) upregulates PPAR-γ by the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. Using Northern-blotting and Western-blotting analyses, we observed that the levels of PPAR-γ mRNA and protein were increased by 2- to 3.5-fold in human aortic smooth muscle cells (HASMCs) treated with PDGF (20 ng/mL). This was abolished by preincubation of HASMCs with a PI3-kinase inhibitor (LY294002, 50 μmol/L), and partially inhibited by a MEK1 inhibitor (U0126, 10 μmol/L), but not affected by a p38 kinase inhibitor (SB202190, 10 μmol/L). In addition, overexpression of the dominant-negative p85 subunit of PI3-kinase or Akt proteins blocked the PDGF-induced PPAR-γ expression. Taken together, our results suggest that PDGF induces PPAR-γ expression in VSMCs by a PI3-kinase/Akt signaling pathway. The characterization of factors and signaling pathways that modulate PPAR-γ expression in VSMCs may have important implications for understanding the pathogenesis of vascular diseases.