Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia

Abstract

Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic insults by specific mechanisms. We tested the hypothesis that IPC attenuates post-ischemic neuronal death in the gerbil hippocampal CA1 region (CA1) throughout hypoxia inducible factor-1α (HIF-1α) and its associated factors such as vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-κB). Lethal ischemia (LI) without IPC increased expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) in CA1 pyramidal neurons at 12 h and/or 1-day post-LI; thereafter, their expressions were decreased in the CA1 pyramidal neurons with time and newly expressed in non-pyramidal cells (pericytes), and the CA1 pyramidal neurons were dead at 5-day post-LI, and, at this point in time, their immunoreactivities were newly expressed in pericytes. In animals with IPC subjected to LI (IPC/LI)-group), CA1 pyramidal neurons were well protected, and expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) were significantly increased compared to the sham-group and maintained after LI. Whereas, treatment with 2ME2 (a HIF-1α inhibitor) into the IPC/LI-group did not preserve the IPC-mediated increases of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) expressions and did not show IPC-mediated neuroprotection. In brief, IPC protected CA1 pyramidal neurons from LI by upregulation of HIF-1α, VEGF, and p-IκB-α expressions. This study suggests that IPC increases HIF-1α expression in CA1 pyramidal neurons, which enhances VEGF expression and NF-κB activation and that IPC may be a strategy for a therapeutic intervention of cerebral ischemic injury.

The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection

“…Meanwhile, NAD + and NADP + both activate K Na 1.2 presumably via this nucleotide-binding domain [298], but it should be noted that pyridine nucleotides can also act on K ATP [299] and K Ca channels [300,301], so this property cannot be used to distinguish these channels. Interestingly, in neurons of both humans and rats, K Na 1.2 transcription is regulated by nuclear factor kappa B (NF-κB) activation [302], which itself is activated by IPC and APC [303–306]. Knockout mice for Kcnt1 , Kcnt2 , and a double knockout are available and have been used to determine the role of these channels in cardioprotection (see below) [89,307].…”

MUC3A Promotes Non-Small Cell Lung Cancer Progress via Activating NFκB Pathway and Attenuates Radiosensitivity

“…In this study, we assume VEGF was regulated in two ways. It has been reported that NFκB signaling induces angiogenesis by increasing the production of VEGF [44][45][46], angiogenesis induced by MUC3A is also mediated by NFκB activation in NSCLC. Radiation-mediate hypoxia triggers HIF-1α transcription and up-regulates VEGF expression [46,47], MUC3A knockdown may enhance radiosensitivity by promoting oxygen stress and impair HIF-1α and VEGF expression level.…”

Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges

“…Hypoxia conditions can trigger the generation of hypoxiainducible factor-1α (HIF-1α), which is an oxygen-sensitive transcription factor. It can be significantly upregulated after cerebral ischemia and then participate in regulating the expression of various genes, thereby triggering various physiological responses (123)(124)(125)(126)(127)(128)(129). IPreC has different effects on the expression of HIF-1α in different cells, and it can increase the expression of HIF-1α in neurons quickly and transiently but slowly and continuously in astrocytes (130).…”

“…However, astrocytic HIF-1α was independent of PHD2, which allows astrocytes to cause long-lasting HIF-1α expression and was rather essential for induction of ischemic tolerance efficiently (132). IPreC can also attenuate neuronal death induced by ischemic insults in the gerbil hippocampal CA1 region (CA1) throughout upregulation of HIF-1α, which enhances vascular endothelial growth factor (VEGF) expression and nuclear factor-kappa B (NF-κB) activation (125).…”