Ligustilide attenuates vascular inflammation and activates Nrf2/HO-1 induction and, NO synthesis in HUVECs

Phytomedicine. 2018 Jan 1:38:12-23. doi: 10.1016/j.phymed.2017.09.022. Epub 2017 Oct 4.

Abstract

Background: Ligustilide is a bioactive phthalide derivative isolated from Cnidii Rhizoma (Cnidium officinale, rhizome) and Angelicae Gigantis Radix (Angelica gigas Nakai, root) which are both medicinal herbs used to treat circulatory disorders. Vascular endothelium is a central spot in developing cardiovascular diseases and chronic vascular inflammation might result in atherosclerosis development.

Purpose: We previously found out that a traditional herbal formula, Samul-Tang (Si-Wu-Tang, containing Cnidii Rhizoma and Angelicae Gigantis Radix), attenuated vascular inflammation in human umbilical vein endothelial cells (HUVECs). However, which compound was responsible for vascular protective action remained unclear. Here, we investigated vascular protective potential of an isolated single compound, (Z)-ligustilide.

Methods: MTT assay, western blotting, immunofluorescence, electrophoretic mobility shift assay was performed. BCECF-AM, CM-H2DCFDA, DAF-FM diacetate were used as a fluorescent indicator.

Results: Ligustilide suppressed HL-60 monocyte adhesion and CAMs (ICAM-1, VCAM-1, E-selectin) expression in HUVECs. Ligustilide significantly inhibited TNF-α-increased production of ROS and activated NF-κB signaling pathway. Also, ligustilide treated HUVECs exhibited significant HO-1 induction via Nrf2 nuclear translocation and endothelial NO synthesis.

Conclusion: Present study demonstrates that ligustilde attenuates vascular inflammation and activate defense system of endothelial cell. Ligustilide is a bioactive compound which might prevent cardiovascular complications such as thrombosis or atherosclerosis.

Keywords: Adhesion molecules; Atherosclerosis; HO-1; HUVECs; Ligustilide; NF-κB; NO synthesis; Nrf2; TNF-α; Vascular inflammation.

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • E-Selectin / metabolism
  • Fluoresceins / metabolism
  • Fluorescent Dyes / metabolism
  • HL-60 Cells
  • Heme Oxygenase-1 / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vasculitis / drug therapy*
  • Vasculitis / metabolism

Substances

  • 2',7'-dichlorodihydrofluorescein diacetate
  • 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate
  • Anti-Inflammatory Agents, Non-Steroidal
  • E-Selectin
  • Fluoresceins
  • Fluorescent Dyes
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NFE2L2 protein, human
  • SELE protein, human
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide
  • ligustilide
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • 4-Butyrolactone