Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12

Abstract

Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia–ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.

Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury

“…4 ER stress can be triggered by various stimuli, such as ischemia, hypoxia, oxidative stress, glucose starvation, and elevated protein synthesis. 3,[5][6][7] Three major ER stress response transmembrane proteins are primarily activated, including protein kinase-like ER kinase (PERK), inositol requiring 1 (IRE1), and activating transcription factor 6 (ATF6), which activate downstream signaling effectors.…”

rAAV8-733-Mediated Gene Transfer of CHIP/Stub-1 Prevents Hippocampal Neuronal Death in Experimental Brain Ischemia

“…8 However, activation of AKT by oxidative stress may facilitate cell death depending on context, 9 indicating that dynamic phosphorylation of AKT may affect several mechanisms related to cell fate. Proteostasis defects after brain ischemia are well documented, including disruption of the ubiquitin-proteasome system (UPS), 10 endoplasmic reticulum (ER) stress, 11,12 and inhibition of global protein synthesis mediated by the phosphorylation of eukaryotic initiation factor-2a (eIF2a) at serine 51 (Ser51). 13 These findings suggest that modulation of key components related to integrity of the proteome may promote neuroprotection after an ischemic insult.…”

Notoginsenoside R1 Protects against Neonatal Cerebral Hypoxic-Ischemic Injury through Estrogen Receptor-Dependent Activation of Endoplasmic Reticulum Stress Pathways

“…In oxygen-glucose deprivation/reoxygenation (OGD/R)-treated cortical cultures, at least 50% of dying cells show morphologic characteristics of apoptosis (Badiola et al, 2011). Therefore, targeting cell apoptosis after HIE may be a promising therapeutic strategy.…”