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iKeap1 activates Nrf2 signaling to protect myocardial cells from oxygen glucose deprivation/re-oxygenation-induced oxidative injury.
- Source :
-
Biochemical & Biophysical Research Communications . Oct2021, Vol. 574, p110-117. 8p. - Publication Year :
- 2021
-
Abstract
- Nuclear factor E2-related factor 2 (Nrf2) activation could efficiently protect myocardial cells from oxygen glucose deprivation/re-oxygenation (OGDR). An ultra-large structure-based virtual screening has discovered iKeap1 as a novel, direct and potent Keap1 inhibitor. Here we found that iKeap1 efficiently activated Nrf2 signaling in H9c2 myocardial cells and primary murine myocardiocytes. iKeap1 induced Keap1-Nrf2 disassociation, cytosol Nrf2 protein stabilization and nuclear translocation. The antioxidant response element (ARE) activity and expression of Nrf2 cascade genes (HO1 , NQO1 and GCLC) were increased in iKeap1-treated myocardial cells. In H9c2 cells and murine myocardiocytes, iKeap1 potently inhibited OGDR-induced oxidative injury by inhibiting reactive oxygen species (ROS) production, mitochondrial depolarization, lipid peroxidation and DNA damage. In addition, OGDR-induced myocardial cell death and apoptosis were largely ameliorated after pretreatment with the novel Keap1 inhibitor. Significantly, in H9c2 cells iKeap1-induced myocardial cytoprotection against OGDR was abolished with Nrf2 silencing or knockout (using CRISPR/Cas9 method). Moreover, CRISPR/Cas9-induced Keap1 knockout led to constitutive activation of Nrf2 cascade and inhibited OGDR-induced oxidative injury. Importantly, iKeap1 was unable to further protect Keap1-knockout H9c2 cells from OGDR. Together, iKeap1 activated Nrf2 signaling to protect myocardial cells from OGDR-induced oxidative injury and cell death. • iKeap1 activates Nrf2 signaling cascade in myocardial cells. • iKeap1 ameliorates OGDR-induced oxidative injury in myocardial cells. • iKeap1 ameliorates OGDR-induced myocardial cell death. • iKeap1-induced myocardial cytoprotection against OGDR requires Nrf2 activation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0006291X
- Volume :
- 574
- Database :
- Academic Search Index
- Journal :
- Biochemical & Biophysical Research Communications
- Publication Type :
- Academic Journal
- Accession number :
- 152249245
- Full Text :
- https://doi.org/10.1016/j.bbrc.2021.08.024