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Activation of Keap1-Nrf2 Signaling by 4-octyl Itaconate Protects Human Umbilical Vein Endothelial Cells From High Glucose

Activation of Keap1-Nrf2 Signaling by 4-octyl Itaconate Protects Human Umbilical Vein Endothelial Cells From High Glucose

Chun Tang, Shengyu Tan, Yiqing Zhang, Lini Dong, Yan Xu

Biochem Biophys Res Commun. 2019 Jan 15;508(3):921-927.

PMID: 30545629

Abstract:

High glucose (HG) induces oxidative injury to cultured human umbilical vein endothelial cells (HUVECs). Recent studies have discovered 4-octyl itaconate (OI) as a novel and cell permeable Nrf2 (nuclear-factor-E2-related factor 2) activator. Its potential activity in HG-treated HUVECs was tested here. In HUVECs OI disrupted Keap1-Nrf2 association, causing Nrf2 protein accumulation and nuclear translocation, as well as transcription and expression of Nrf2-ARE-dependent genes, including HO1, NQO1 and GCLM. Significantly, pretreatment with OI potently inhibited HG (40 mM glucose)-induced death and apoptosis of HUVECs. Moreover, OI potently inhibited HG-induced reactive oxygen species (ROS) production, lipid peroxidation, superoxide accumulation and mitochondrial depolarization in HUVECs. Activation of Nrf2 is required for OI-induced cytoprotection in HUVECs. Nrf2 shRNA or knockout (by CRISPR/Cas9 method) reversed OI-mediated HUVEC protection against HG. Further studies showed that Keap1 silencing or Cys151S mutation mimicked and nullified OI-induced activity in HUVECs. Taken together, we conclude that OI activates Keap1-Nrf2 signaling to protect HUVECs from HG.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP3133162	4-Octyl itaconate		3133-16-2	Price

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