(-)-7(S)-hydroxymatairesinol protects against tumor necrosis factor-α-mediated inflammation response in endothelial cells by blocking the MAPK/NF-κB and activating Nrf2/HO-1

Phytomedicine. 2017 Aug 15:32:15-23. doi: 10.1016/j.phymed.2017.04.005. Epub 2017 Apr 10.

Abstract

Background: Endothelial inflammation is an increasingly prevalent condition in the pathogenesis of many cardiovascular diseases. (-)-7(S)-hydroxymatairesinol (7-HMR), a naturally occurring plant lignan, possesses both antioxidant and anti-cancer properties and therefore would be a good strategy to suppress tumor necrosis factor-α (TNF-α)-mediated inflammation in vascular endothelial cells (VECs).

Purpose: The objective of this study is to evaluate for its anti-inflammatory effect on TNF-α-stimulated VECs and underling mechanisms.

Study design/methods: The effect of the 7-HMR on suppression of TNF-α-induced inflammation mediators in VECs were determined by qRT-PCR and Western blot. MAPKs and phosphorylation of Akt, HO-1 and NF-κB p65 were examined using Western blot. Nuclear localisation of NF-κB was also examined using Western blot and immunofluorescence.

Results: Here we found that 7-HMR could suppress TNF-α-induced inflammatory mediators, such as vascularcelladhesion molecule-1, interleukin-6 and inducible nitric oxide synthase expression both in mRNA and protein levels, and concentration-dependently attenuated reactive oxidase species generation. We further identified that 7-HMR remarkably induced superoxide dismutase and heme oxygenase-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (keap1) and up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, 7-HMR time- and concentration-dependently attenuated TNF-α-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) and Akt, but not p38, or c-Jun N-terminal kinase 1/2. Moreover, 7-HMR significantly suppressed TNF-α-mediated nuclear factor-κB (NF-κB) activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65.

Conclusion: Our results demonstrated that 7-HMR inhibited TNF-α-stimulated endothelial inflammation, at least in part, through inhibition of NF-κB activation and upregulation of Nrf2-antioxidant response element signaling pathway, suggesting 7-HMR might be used as a promising vascular protective drug.

Keywords: (-)-7(S)-hydroxymatairesinol; NF-κB; Reactive oxygen species; Vascular inflammation; heme oxygenase-1.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antioxidant Response Elements / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Heme Oxygenase-1 / metabolism
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation Mediators / metabolism
  • Interleukin-6 / metabolism
  • Lignans / pharmacology*
  • Male
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Rats
  • Tumor Necrosis Factor-alpha / adverse effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Inflammation Mediators
  • Interleukin-6
  • Lignans
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • hydroxymatairesinol
  • Heme Oxygenase-1
  • Extracellular Signal-Regulated MAP Kinases