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Atheroprotective effects of 17beta-estradiol are mediated by PPARgamma in human coronary artery smooth muscle cells

Session Poster Session 1

Speaker Julian Jehle

Event : ESC Congress 2019

  • Topic : basic science
  • Sub-topic : Basic Science - Vascular Biology and Physiology: Signal Transduction, Mechano-Transduction
  • Session type : Poster Session

Authors : J Jehle (Bonn,DE), V Tiyerili (Bonn,DE), S Adler (Bonn,DE), K Groll (Bonn,DE), G Nickenig (Bonn,DE), UM Becher (Bonn,DE)

Authors:
J Jehle1 , V Tiyerili1 , S Adler1 , K Groll1 , G Nickenig1 , UM Becher1 , 1University Hospital Bonn, Department of Cardiology - Bonn - Germany ,

Citation:

Background: 17ß-estradiol (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-? (PPAR?) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPAR? is implicated in mediating vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC).

Methods: Primary HCASMC were purchased and stimulated with E2 [10 nM], the selective estrogen receptor a (ERa) agonist propylpyrazole triol (PPT) [50 nM] and the selective ERa antagonist methyl-piperidino-pyrazole (MPP) [1 µM], respectively. Changes in PPAR? mRNA and protein expression upon stimulation of ERa were assessed by qPCR and Western blot analyses. Nuclear PPAR? protein expression and DNA binding affinity was assessed after the isolation of the nuclear protein fraction. Hereafter, HCASMC were incubated with E2, PPAR?-antagonist GW9662 [1 µM – 30 µM], or both. HCASMC proliferation was assessed by nuclear BrdU staining and reactive oxygen species (ROS) formation was assessed by L-012- and DCF-DA assays.

Results: E2 significantly increased PPAR? expression in HCASMC (1.95 ± 0.41 –fold; n = 5; p = 0.0335). This effect was mimicked by ERa agonist PPT (1.63 ± 0.27 –fold; n = 7; p = 0.0489) and was abrogated by co-incubation with ERa antagonist MPP (1.17 ± 0.18 –fold; n = 3; pvs. control > 0.05). Nuclear PPAR? expression was enhanced by E2 (1.53 ± 0.16 –fold; n = 4; pvs. control = 0.0074; Fig. 2A) whereas PPAR?’s DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94 ± 0.11 –fold; n = 4; pvs. control > 0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPAR? (0.24 ± 0.09 –fold; n = 3; pvs. E2 = 0.0017), arguing for a PI3K/Akt-dependent activation by E2. The role of PPAR? in mediating vasculoprotective effects of E2 was assessed in functional assays using PPAR?-antagonist GW9662. E2 diminished HCASMC proliferation which was restored by GW9662. While E2 only slightly decreased ROS production by HCASMC, GW9662 significantly increased ROS levels (1,036 ± 169 RLU x s-1 x cell-1 versus 561 ± 99 RLU x s-1 x cell-1; n = 5-6; p = 0.0287).

Conclusion: In summary, the present study identifies PPAR? as a downstream mediator of E2-related atheroprotective effects in HCASMC. 17ß-estradiol regulates vascular PPAR?-expression in HCASMC via the ERa receptor and the PI3K/Akt pathway. PPAR? agonism might be a promising therapeutic strategy to prevent cardiovascular events in postmenopausal women with depleted E2 plasma levels.

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