Activation of Keap1-Nrf2 signaling by 4-octyl itaconate protects human umbilical vein endothelial cells from high glucose.
Biochem Biophys Res Commun
; 508(3): 921-927, 2019 01 15.
Article
en En
| MEDLINE
| ID: mdl-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 (40â¯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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Succinatos
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Factor 2 Relacionado con NF-E2
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Células Endoteliales de la Vena Umbilical Humana
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Proteína 1 Asociada A ECH Tipo Kelch
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Glucosa
Límite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2019
Tipo del documento:
Article
País de afiliación:
China