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

Vascular diseases such as atherosclerosis are characterized by abnormal acc umulation of vascular smooth muscle cells (VSMCs) within the intimal lining . The intimal VSMCs exhibit an increased expression of peroxisome prolifera tor-activated receptor gamma (PPAR gamma), and the administration of pharma cological PPAR gamma agonists attenuates vascular lesion formation. The fac tors that regulate PPAR gamma expression in the vasculature are poorly defi ned. Here we report that platelet-derived growth factor (PDGF) upregulates PPAR gamma by the phosphatidylinositol 3-kinase (PI3-kinase)/ Akt signaling pathway. Using Northern-blotting and Western-blotting analyses, we observe d that the levels of PPAR gamma mRNA and protein were increased by 2- to 3. 5-fold in human aortic smooth muscle cells (HASMCs) treated with PDGF (20 n g/mL). This was abolished by preincubation of HASMCs with a PI3-kinase inhi bitor (LY294002, 50 mu mol/L), and partially inhibited by a MEK1 inhibitor (U0126, 10 mu mol/L), but not affected by a p38 kinase inhibitor (SB202190, 10 mu mol/L). In addition, overexpression of the dominant-negative p85 sub unit of PI3-kinase or Akt proteins blocked the PDGF-induced PPAR gamma expr ession. Taken together, our results suggest that PDGF induces PPAR gamma ex pression in VSMCs by a PI3-kinase/Akt signaling pathway. The characterizati on of factors and signaling pathways that modulate PPAR gamma expression in VSMCs may have important implications for understanding the pathogenesis o f vascular diseases.