RESUMEN

INTRODUCTION: 17ß-oestradiol (E2) mediates vasculoprotection in various preclinical and clinical models of atherosclerosis and neointimal hyperplasia. However, the molecular mechanisms underlying these effects are still not fully elucidated. Previous studies have demonstrated the essential role of the peroxisome-proliferator-activated-receptor-γ (PPARγ) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPARγ mediates vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC). MATERIAL AND METHODS: Primary HCASMC were stimulated with E2 (10 nM), the selective oestrogen receptor α (ERα) agonist propylpyrazole triol (PPT) (50 nM) and the selective ERα antagonist methyl-piperidino-pyrazole (MPP) (1 µM), respectively. Changes in PPARγ mRNA, protein expression, and DNA binding affinity were assessed. RESULTS: E2 significantly increased PPARγ expression in HCASMC (1.95 ±0.41-fold; n = 5; p = 0.0335). This effect was mimicked by ERα agonist PPT (1.63 ±0.27-fold; n = 7; p = 0.0489) and was abrogated by co-incubation with ERα antagonist MPP (1.17 ±0.18-fold; n = 3; p vs. control > 0.05). PPARγ-DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94 ±0.11-fold; n = 4; p vs. control > 0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPARγ (0.24 ±0.09-fold; n = 3; p vs. E2 = 0.0017). CONCLUSIONS: The present study identifies PPARγ as an important downstream mediator of E2-related atheroprotective effects in HCASMC. PPARγ agonism might be a promising therapeutic strategy to prevent neointimal hyperplasia and consecutive cardiovascular events in postmenopausal women with depleted E2 plasma levels.