Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/eIF2α/ATF4/CHOP Signaling Pathway

Abstract

Apoptosis induced by endoplasmic reticulum (ER) stress plays a crucial role in mediating brain damage after ischemic stroke. Recently, Hes1 (hairy and enhancer of split 1) has been implicated in the regulation of ER stress, but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear. In this study, using a mouse model of ischemic stroke via transient middle cerebral artery occlusion (tMCAO), we found that Hes1 was induced following brain injury, and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome, suggesting that Hes1 knockdown exacerbates ischemic stroke. In addition, mechanistically, Hes1 knockdown promoted apoptosis and activated the PERK/eIF2a/ATF4/ CHOP signaling pathway after tMCAO. These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis. Furthermore, inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO, implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/ eIF2a/ATF4/CHOP signaling pathway. Taken together, these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis, thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

“…Excessive ER stress induces neuronal apoptosis, and in turn aggravates neuronal damage caused by cerebral ischemia [32]. Under this circumstance, GRP78 acts as a sensor and activates PERK and IRE1α, after which downstream signaling molecules such as eIF2α, ATF4, and CHOP are activated [33]. In the present study, we established an OGD cellular model and found that GRP78 was up-regulated at the early stage of hypoxia (3 h) and continued to increase in a time-dependent manner (Fig.…”

Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress

“…Prolonged environmental stress triggers signal transduction pathways that lead to apoptosis and thereby heighten pathological processes, leading to cerebral damage (Chi et al, 2019 ). Endoplasmic reticulum stress exerts its vital role in stroke-induced neural apoptosis (Mohammed Thangameeran et al, 2020 ) through activation of downstream CCAATenhancer-binding protein homologous protein (CHOP) and caspase-12 (Chi et al, 2019 ; Chu et al, 2019 ; Li Y. et al, 2020 ). SIRT1 is a nicotine adenine dinucleotide (NAD+)-dependent enzyme that deacetylates numerous transcription factors in response to ischemic stress and is involved in various biological pathways (Chen et al, 2005 ).…”

Asiaticoside Alleviates Cerebral Ischemia-Reperfusion Injury via NOD2/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Factor kappa B (NF-κB) Signaling Pathway

“…The time window of mechanical thrombectomy is only 6 h and is not sufficient. The timely restoration of blood flow results in oxidative stress, inflammatory responses, and endoplasmic reticulum stress [8][9][10]. Therefore, it is crucial to find a way to avoid or attenuate cerebral ischemia-reperfusion injury to improve treatment of ischemia stroke.…”