Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation‐evoked ischemic injury in neuron by suppressing mTOR‐mediated excessive autophagy

Abstract

Cerebral ischemia/reperfusion (I/R) typically occurs after mechanical thrombectomy to treat ischemic stroke, generation of reactive oxygen species (ROS) after reperfusion may result in neuronal insult, ultimately leading to disability and death. Regulated in development and DNA damage responses 1 (REDD1) is a conserved stress response protein under various pathogenic conditions. Recent research confirms the controversial role of REDD1 in injury processes. Nevertheless, the role of REDD1 in cerebral I/R remains poorly defined. In the current study, increased expression of REDD1 was observed in neurons exposed to simulated I/R via oxygen glucose deprivation/reoxygenation (OGD/R) treatment. Knockdown of REDD1 enhanced OGD/R‐inhibited cell viability, but suppressed lactate dehydrogenase (LDH) release in neurons upon OGD/R. Simultaneously, suppression of REDD1 also antagonized OGD/R‐evoked cell apoptosis, Bax expression, and caspase‐3 activity. Intriguingly, REDD1 depression abrogated neuronal oxidative stress under OGD/R condition by suppressing ROS, MDA generation, and increasing antioxidant SOD levels. Further mechanism analysis corroborated the excessive activation of autophagy in neurons upon OGD/R with increased expression of autophagy‐related LC3 and Beclin‐1, but decreased autophagy substrate p62 expression. Notably, REDD1 inhibition reversed OGD/R‐triggered excessive neuronal autophagy. More importantly, depression of REDD1 also elevated the expression of p‐mTOR. Preconditioning with mTOR inhibitor rapamycin engendered not only a reduction in mTOR activation, but also a reactivation of autophagy in REDD1 knockdown‐neurons upon OGD/R. In addition, blocking the mTOR pathway muted the protective roles of REDD1 inhibition against OGD/R‐induced neuron injury and oxidative stress. Together these data suggested that REDD1 may regulate I/R‐induced oxidative stress injury in neurons by mediating mTOR‐autophagy signaling, supporting a promising therapeutic strategy against brain ischemic diseases.

Ginsenoside Re Treatment Attenuates Myocardial Hypoxia/Reoxygenation Injury by Inhibiting HIF-1α Ubiquitination

“…In our study, ginsenoside Re treatment increased the mRNA level of GLUT1, suggesting that ginsenoside Re improves energy metabolism in cardiomyocytes following H/R. REDD1 is an essential regulator of cell growth, and a low level of REDD1 expression is associated with cell apoptosis (Sun and Yue, 2019). Our study showed that ginsenoside Re treatment significantly increased the mRNA level of REDD1, indicating that the effects of ginsenoside Re on cardiomyocyte H/R injury are related to the inhibition of cell apoptosis.…”

Calycosin-7-O-β-D-glucoside Attenuates OGD/R-Induced Damage by Preventing Oxidative Stress and Neuronal Apoptosis via the SIRT1/FOXO1/PGC-1α Pathway in HT22 Cells

“…Despite tremendous advances in the theoretical understanding of ischemic stroke in the past several decades, stroke remains the third leading cause of death and permanent disability [35]. Oxygen glucose deprivation reperfusion is an in vitro model that mimics the in vivo process of a series of pathological reactions initiated by ischemia-reperfusion [36, 37].…”

Artemisinin attenuated oxidative stress and apoptosis by inhibiting autophagy in MPP+-treated SH-SY5Y cell

“…However, on the other hand, with the continuous enhancement of autophagy, it can directly induce the death of oxidized cells and further damage to mitochondria, thereby reversely aggravating the oxidative stress damage of cells 29 . By monitoring the levels of autophagy proteins LC3II/I, Beclin1 and P62, we found that MPP + increased the autophagy level, and pre-treatment with ART decreased the autophagy level compared with MPP + .…”