Evidence that collaboration between HIF-1α and Notch-1 promotes neuronal cell death in ischemic stroke

Abstract

Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1α (HIF-1α), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1α pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, γ-secretase, and a HIF-1α inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1α further decreased neuronal death. HIF-1α and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1α in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1α inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1α also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of γ-secretase and HIF-1α exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1α collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…Moreover, hypoxic preconditioning induces stroke tolerance in mice via HIF-1a signaling Wacker et al, 2012). Other studies, however, show that deletion or inhibition of HIF-1a resulted in reduced brain damage after ischemic stroke or hypoxic conditions, suggesting a detrimental role of HIF-1a (Helton et al, 2005;Chen et al, 2009a;Cheng et al, 2014).…”

Hypoxia inducible factor-1α expression is associated with hippocampal apoptosis during epileptogenesis

“…Correlation analysis in this study could offer a strong evidence to reveal the influence of HIF-1α on hippocampal apoptosis in the rat model of epilepsy. It has been demonstrated that HIF-1a can accumulate enough to activate a pathway to apoptosis on the condition of hypoxia (Berger et al, 2013;Cheng et al, 2014). However, there is no evidence to support that HIF-1α is able to exercise influence on hippocampal apoptosis in the epileptic model.…”

Molecular mechanisms of Notch1-mediated neuronal cell death in ischemic stroke

“…It was recently reported that activity of γ-secretase and the resulting Notch1 activation, may endanger neurons in ischemic stroke by modulating pathways to increase vulnerability to apoptosis and by activating microglial cells and stimulating the infiltration of pro-inflammatory leukocytes Li et al 2012;Wang et al 2012). Furthermore it was shown in previous studies in this thesis and studies from other groups that Notch1 signaling endangers neurons after ischemic stroke by modulating nuclear factor-κB (NF-κB), pro-death protein Bim, hypoxia inducible factor-1α (HIF-1α) and caspase-3 Cheng et al 2014). …”

“…We have shown previously that γ-secretase activity and subsequent Notch signaling are elevated in the brain after ischemic stroke in vivo . Furthermore, γ-secretase activity was elevated in cultured primary neurons after ischemic conditions, and γ-secretase-mediated Notch signaling contributes to neuronal death in ischemic stroke by modulating the NF-κB, pro-death protein Bim, calcium signaling, HIF1α, and caspase pathways Cheng et al, 2014). Recent evidence indicates that Notch may mediate several of its physiological responses through MAPK pathways (Stockhausen et al, 2005;Kondoh et al, 2007;.…”

“…Overexpression of Pin1 increased NICD expression and further potentiated Notch-mediated neuronal cell death in simulated ischemia. Furthermore, binding of Pin1 to NICD augmented NICD accumulation and increased NICD stability by blocking the ubiquitin-mediated proteolysis of NICD (Baik et al 2014). …”