Journal
CIRCULATION RESEARCH
Volume 89, Issue 11, Pages 1058-1064Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh2301.099642
Keywords
platelet-derived growth factor; peroxisome proliferator-activated receptor gamma; phosphatidylinositol 3-kinase; signaling pathway; vascular smooth muscle cells
Funding
- NHLBI NIH HHS [UH1 HL03676-02] Funding Source: Medline
- NIGMS NIH HHS [GMS S06GM08248] Funding Source: Medline
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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 gamma (PPAR gamma), and the administration of pharmacological PPAR gamma agonists attenuates vascular lesion formation. The factors that regulate PPAR gamma expression in the vasculature are poorly defined. 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 observed 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 ng/mL). This was abolished by preincubation of HASMCs with a PI3-kinase inhibitor (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 subunit of PI3-kinase or Akt proteins blocked the PDGF-induced PPAR gamma expression. Taken together, our results suggest that PDGF induces PPAR gamma expression in VSMCs by a PI3-kinase/Akt signaling pathway. The characterization of factors and signaling pathways that modulate PPAR gamma expression in VSMCs may have important implications for understanding the pathogenesis of vascular diseases.
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