Zedoarondiol Attenuates Endothelial Cells Injury Induced by Oxidized Low-Density Lipoprotein via Nrf2 Activation

Cell Physiol Biochem. 2018;48(4):1468-1479. doi: 10.1159/000492257. Epub 2018 Jul 31.

Abstract

Background/aims: Zedoarondiol, a sesquiterpene lactone compound, showed an anti-proliferative activity on vascular smooth muscle cells in our previous study. However, whether it has a beneficial effect on endothelial cells injury induced by oxidized low-density lipoprotein (ox-LDL) remains unclear. This study was designed to investigate the protective effect of zedoarondiol on ox-LDL-induced injury of endothelial cells and explored its underlying mechanism.

Methods: The protective effect of zedoarondiol on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) injury were evaluated by Cell Counting Kit-8 (CCK-8) assay and released lactic dehydrogenase (LDH) activity assay. Oxidative stress was determined by malonedialdehyde (MDA) content and superoxide dismutase (SOD) activity. The level of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescin diacetate (DCFH-DA) staining. The culture supernatant was collected for enzyme linked immune-sorbent assays (ELISA) of interleukine-1β (IL-1β), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Immunofluorescence staining was used to observe NF-E2-related factor 2 (Nrf2) translocation. Western blotting was performed to determine the expression of IL-1β, TNF-α, MCP-1, Kelch-like ECH associated protein 1 (Keap1), heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO1), and Nrf2.

Results: Zedoarondiol attenuated HUVECs injury, up-regulated SOD activity, suppressed formation of MDA and ROS, and secretion and protein expression of IL-1β, TNF-α, and MCP-1 in injured HUVECs induced by ox-LDL. Zedoarondiol induced nuclear Nrf2 translocation from cytoplasm into nucleus and up-regulated expression of HO-1, NQO1, and Nrf2 in nucleus. All-trans-retinoic acid (ATRA), an inhibitor of Nrf2, abolished zedoarondiol-mediated anti-oxidative effect.

Conclusion: Zedoarondiol attenuates ox-LDL-induced endothelial cells injury by inhibiting oxidative stress and inflammation via Nrf2/HO-1 pathway, suggesting that zedoarondiol might be meaningful on prevention and treatment of atherosclerosis.

Keywords: Endothelial cells; Inflammation; Nrf2; Oxidative stress; Zedoarondiol.

MeSH terms

  • Cell Survival / drug effects
  • Chemokine CCL2 / analysis
  • Heme Oxygenase-1 / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Interleukin-1beta / analysis
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Lactones / pharmacology*
  • Lipoproteins, LDL / toxicity*
  • Malondialdehyde / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Sesquiterpenes / pharmacology*
  • Superoxide Dismutase / metabolism
  • Tretinoin / pharmacology
  • Tumor Necrosis Factor-alpha / analysis

Substances

  • Chemokine CCL2
  • Interleukin-1beta
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Lactones
  • Lipoproteins, LDL
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • Sesquiterpenes
  • Tumor Necrosis Factor-alpha
  • oxidized low density lipoprotein
  • zedoarondiol
  • Malondialdehyde
  • Tretinoin
  • L-Lactate Dehydrogenase
  • Heme Oxygenase-1
  • Superoxide Dismutase
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human