Activation of hypoxia-inducible factor-1α in rat brain after perinatal anoxia: role of body temperature

Abstract

Transcriptional hypoxia-inducible factor-1α (HIF-1α) plays the fundamental role in adaptive processes in response to hypoxia. Specific HIF-1α target genes are involved in glycolysis, erythropoiesis and angiogenesis to promote survival. In our previous study we have demonstrated that naturally low body temperature of newborn rats protects them against damage due to perinatal hypoxia. Therefore, our experiments aimed at checking the effects of body temperature during simulated perinatal anoxia on subsequent changes of expression of HIF-1α and its specific target genes such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in the rat brain. Two-day old Wistar rats were divided into three temperature groups: normothermic -33 °C, hyperthermic -37 °C and extremely hyperthermic -39 °C. The temperature was controlled 15 min before start and continued during 10 min of anoxia as well as for 2 h post-anoxia. HIF-1α was analysed by Western blot and immunofluorescence and mRNA levels of HIF-1α and its downstream genes (VEGF, EPO) were quantified by qRT-PCR. Thermal conditions during neonatal anoxia affected the hippocampal and neocortical level of HIF-1α protein. Physiological body temperature of newborn rats led to prominent accumulation of cerebral HIF-1α protein and significant upregulation of VEGF and EPO mRNA. In contrast, anoxia-induced HIF-1α activation at elevated body temperatures was less pronounced. Since HIF-1α and EPO have recently been regarded as promising therapeutical targets against brain lesions due to hypoxia/ischemia, presented data imply that in order to achieve a full effect of neuroprotection, the thermal conditions during and after the insult should be taken into consideration.

Thermal conditions during neonatal anoxia affect the endogenous level of brain‐derived neurotrophic factor

“…By contrast, our up‐to‐date studies have shown that neonatal anoxia combined with hyperthermia intensified the postanoxic oxidative stress (Kletkiewicz, Rogalska, et al, ), depleted the cerebral pool of antioxidant enzymes and low molecular weight antioxidants (Kletkiewicz, Nowakowska, et al, ). Consistently, we have also shown that thermal stress conditions (hyperthermic, extremely hyperthermic) decreased the HIF‐1α level in the hippocampus of animals exposed to anoxia (Kletkiewicz, Hyjek, Jaworski, Nowakowska, & Rogalska, ). On the other hand, neuroprotective effects of decreased temperature in newborn rats are multifunctional (Cerio et al, ).…”

“…Anoxia was induced in 2‐day‐old Wistar rats ( n = 57) using the procedure previously adapted and described in earlier papers (Kletkiewicz et al, ; Kletkiewicz, Nowakowska, et al, ; Kletkiewicz, Rogalska, et al, ). Briefly, prior to experiments, thermocouples connected to the recording system (3000‐E52 Iso‐Thermex Interface & Software, USA) were inserted 5 mm into the colon of the rat pups.…”

EPO activates PI3K-IKKα-CDK1 signaling pathway to promote the proliferation of Glial Cells under hypoxia environment

“…HIF-1, which is composed of two subunits, α and β, can participate in glycolysis metabolism and erythropoiesis and is relatively stable during hypoxia ( Semenza, 2014 ). Some studies have shown that HIF-1α in newborn rats significantly increases during hypoxia ( Kletkiewicz et al, 2018 ). Chu et al (2016 ) used CoCl 2 to establish a hypoxia model of breast cancer cells and found that the expression of HIF-1α mRNA was increased in those cells.…”

The Immunopathogenesis of Neuroinvasive Lesions of SARS-CoV-2 Infection in COVID-19 Patients

“…Interestingly Hypoxia can impair metabolic pathways in the brain as well and activate immune cells that are usually maintained in a resting state during normoxia. The hypoxia microenvironment in the brain actives hypoxia inducible factor 1 (HIF-1α) which is a key regulator of oxygen homeostasis and triggers adoptive responses under hypoxic conditions (73). HIF-1α down regulates the expression of ACE2 and transmembrane protease serine 2 (TMPRSS2) and so can exert a protective effect by blocking of the cell entry gate of SARS-CoV-2 (74,75).…”