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Effects of bezafibrate on the expression of endothelial nitric oxide synthase gene and its mechanisms in cultured bovine endothelial cells

  • Yan Wang
    Affiliations
    Cardiovascular Division of Internal Medicine Department and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
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  • Yan Wang
    Affiliations
    Cardiovascular Division of Internal Medicine Department and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
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  • Qi Yang
    Affiliations
    Cardiovascular Division of Internal Medicine Department and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
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  • Jiang Tao Yan
    Affiliations
    Cardiovascular Division of Internal Medicine Department and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
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  • Chunxia Zhao
    Affiliations
    Cardiovascular Division of Internal Medicine Department and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
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  • Katherine Cianflone
    Affiliations
    Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Center, Montreal, Que., Canada H3A 1A1
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  • Dao Wen Wang
    Correspondence
    Corresponding author. Tel.: +86 27 8366 2842; fax: +86 27 8366 2842.
    Affiliations
    Cardiovascular Division of Internal Medicine Department and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
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      Abstract

      Objective

      Peroxisome proliferator-activated receptors alpha (PPARα) is a target gene for atherosclerosis and cardiovascular diseases. However, effects of PPARα on endothelial nitric oxide synthase (eNOS) remain unknown. We investigated the eNOS regulation by bezafibrate, a ligand of PPARα, and involved signaling pathways.

      Methods and results

      Firstly, in cultured bovine aorta endothelial cells (BAEC), bezafibrate significantly upregulated eNOS at protein, mRNA levels and NO production, respectively, in a concentration-dependent fashion (50–200 μM). Next, the effects of bezafibrate on signal pathways and eNOS mRNA stability in BAEC were investigated. Results showed that bezafibrate induced phosphorylation of MAPK. Inhibitors of PPARα, PI3 kinase and MAPK, respectively, markedly attenuate bezafibrate-induced upregulation of eNOS. Bezafibrate incubation increased eNOS mRNA half-life, activated eNOS promoter, enhanced phosphorylation of eNOS ser-1179 site, and decreased phosphorylation of eNOS thr-497 site via activating ERK and Akt.

      Conclusions

      Bezafibrate can upregulate eNOS expression, enhance phosphorylation of eNOS ser-1179, increase NO production and transcription level and stability of eNOS mRNA through pathway dependent of PPARα and nongenomic effects mediated by MAPK and PI3K pathways. Hence, PPARα ligands exert direct benefits on vessel endothelial functions through an increase in eNOS expression level and phosphorylation of eNOS ser-1179. This mechanism provides additional anti-atherosclerotic and anti-hypertension benefits of bezafibrate in addition of lipid-lowering effects.

      Keywords

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