Retinoic acid decreases nitric oxide production in endothelial cells: A role of phosphorylation of endothelial nitric oxide synthase at Ser 1179

Du Hyong Cho, Yoon Jung Choi, Sangmee Ahn Jo, Jae Hwan Nam, Sung Chul Jung, Inho Jo

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The effects of retinoic acid (RA) on nitric oxide (NO) production are controversial. Furthermore, it has never been studied whether these effects are mediated by direct modulation of phosphorylation of endothelial nitric oxide synthase (eNOS). Using bovine aortic endothelial cells, we found that all-trans RA (atRA) dose- and time-dependently decreased NO production without alteration in eNOS expression. This decrease was accompanied by reduction in eNOS-Ser 1179 phosphorylation. However, atRA did not alter the phosphorylation of eNOS-Ser 116 or eNOS-Thr 497. Concurrently, atRA also decreased the expressions of vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1, and Akt phosphorylation. Co-treatment with troglitazone, an activator of VEGF expression, reversed the atRA-induced reductions in eNOS-Ser 1179 phosphorylation and NO production, with concomitant restoration in VEGF expression. Direct treatment with VEGF also reversed these inhibitory effects, suggesting an important role for VEGF. Nonetheless, the RARα antagonist Ro 41-5253 did not block all the inhibitory effects of atRA, indicating that these inhibitory effects are not mediated by the RA response element (RARE). Thus, atRA decreases eNOS-Ser 1179 phosphorylation through a mechanism that depends on VEGF-KDR/Flk-1-mediated Akt phosphorylation but is independent of RARE, leading to reduction in NO production.

Original languageEnglish
Pages (from-to)703-710
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume326
Issue number4
DOIs
StatePublished - 28 Jan 2005

Keywords

  • All-trans retinoic acid
  • Endothelial cells
  • Endothelial nitric oxide synthase
  • Nitric oxide
  • Phosphorylation
  • Vascular endothelial growth factor

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