Survival In Hypoxia Research Articles

Differential regulation of HIF‐mediated pathways increases mitochondrial metabolism and ATP production in hypoxic osteoclasts

Inappropriate osteoclast activity instigates pathological bone loss in rheumatoid arthritis. We have investigated how osteoclasts generate sufficient ATP for the energy-intensive process of bone resorption in the hypoxic microenvironment associated with this rheumatic condition. We show that in human osteoclasts differentiated from CD14+ monocytes, hypoxia (24 h, 2% O2): (a) increases ATP production and mitochondrial electron transport chain activity (Alamar blue, O2 consumption); (b) increases glycolytic flux (glucose consumption, lactate production); and (c) increases glutamine consumption. We demonstrate that glucose, rather than glutamine, is necessary for the hypoxic increase in ATP production and also for cell survival in hypoxia. Using siRNA targeting specific isoforms of the hypoxia-inducible transcription factor HIF (HIF-1α, HIF-2α), we show that employment of selected components of the HIF-1α-mediated metabolic switch to anaerobic respiration enables osteoclasts to rapidly increase ATP production in hypoxia, while at the same time compromising long-term survival. We propose this atypical HIF-driven metabolic pathway to be an adaptive mechanism to permit rapid bone resorption in the short term while ensuring curtailment of the process in the absence of re-oxygenation. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia

Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia.

Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling.

BackgroundProlonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA) characterized by nightly intermittent hypoxia (IH). This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated.MethodsPurified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH) using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis.ResultsCompared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated the IH-induced Mcl-1 increase. In SH, only p38MAPK inhibition decreased Mcl-1 expression. Similar to neutrophils of healthy subjects exposed to IH (0.97± 0.2), in OSA neutrophils, Bax/Mcl-1 ratio was significantly lower compared to normoxic controls (1.0±0.5 vs.1.99±0.3, p=0.015), and Bax did not co-localize with mitochondria.ConclusionsThese findings suggest that decreased Bax/Mcl-1 balance promotes neutrophil survival in IH in-vitro as well as in OSA patients. Moreover, Bax/Mcl-1 protein function in IH and SH might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH.

Cardiac repair with thymosin β4 and cardiac reprogramming factors

Heart disease is a leading cause of death in newborns and in adults. We previously reported that the G-actin-sequestering peptide thymosin β4 promotes myocardial survival in hypoxia and promotes neoangiogenesis, resulting in cardiac repair after injury. More recently, we showed that reprogramming of cardiac fibroblasts to cardiomyocyte-like cells in vivo after coronary artery ligation using three cardiac transcription factors (Gata4/Mef2c/Tbx5) offers an alternative approach to regenerate heart muscle. We have combined the delivery of thymosin β4 and the cardiac reprogramming factors to further enhance the degree of cardiac repair and improvement in cardiac function after myocardial infarction. These findings suggest that thymosin β4 and cardiac reprogramming technology may synergistically limit damage to the heart and promote cardiac regeneration through the stimulation of endogenous cells within the heart.

Time‐of‐flight SIMS as a novel approach to unlocking the hypoxic properties of cancer

It is known that hypoxia‐inducible factor 1 (HIF‐1) activity results in the coordinated up‐regulation of a large number of proteins that facilitate cell survival in tumours; however, the effect of HIF‐1 on cancer metabolism is less well characterised. With knowledge of the specific effect of HIF‐1 on cancer metabolism, biomarkers could be identified for which new drugs could be targeted. Time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) offers the potential to analyse intact cells in situ and has a mass spectral coverage that is applicable to metabolic profiling. It has been used to analyse the effects of HIF‐1 on multicellular tumour models. Multicellular tumour spheroids (MTSs) have been cultured from human colon carcinoma cells with and without the expression of HIF‐1, and the surface of the cross sections of each MTS has been analysed. Because metabolic profiling is an emerging field in ToF‐SIMS, there is a requirement to determine which metabolites can be detected using this technique and which of those can be identified in complex mixtures within biological samples. For this, a selection of metabolites have been analysed, and the ToF‐SIMS standard spectra acquired have been used to localise metabolites in MTS sections. The comparison of metabolic profiles of MTSs with and without the expression of HIF‐1 has elucidated potential biomarkers for tumour survival in hypoxia, some of which may be HIF‐1 regulated. Copyright © 2012 John Wiley & Sons, Ltd.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Hypoxia-Adaptation Involves Mitochondrial Metabolic Depression and Decreased ROS Leakage

Through long-term laboratory selection, we have generated a Drosophila melanogaster population that tolerates severe, normally lethal, level of hypoxia. This strain lives perpetually under severe hypoxic conditions (4% O2). In order to shed light on the mechanisms involved in this adaptation, we studied the respiratory function of isolated mitochondria from the thorax of hypoxia-adapted flies (AF) using polarographic oxygen consumption while monitoring superoxide generation by electron paramagnetic resonance (EPR) techniques. AF mitochondria exhibited a significant 30% decrease in respiratory rate during state 3, while enhancing the resting respiratory rate during State 4-oligo by 220%. The activity of individual electron transport complexes I, II and III were 107%, 65%, and 120% in AF mitochondria as compared to those isolated from control flies. The sharp decrease in complex II activity and modest increase in complexes I and III resulted in >60% reduction in superoxide leakage from AF mitochondria during both NAD+-linked state 3 and State 4-oligo respirations. These results provide evidence that flies with mitochondria exhibiting decreased succinate dehydrogenase activity and reduced superoxide leakage give flies an advantage for survival in long-term hypoxia.

Expression of a Truncated Active Form of VDAC1 in Lung Cancer Associates with Hypoxic Cell Survival and Correlates with Progression to Chemotherapy Resistance

Resistance to chemotherapy-induced apoptosis of tumor cells represents a major hurdle to efficient cancer therapy. Although resistance is a characteristic of tumor cells that evolve in a low oxygen environment (hypoxia), the mechanisms involved remain elusive. We observed that mitochondria of certain hypoxic cells take on an enlarged appearance with reorganized cristae. In these cells, we found that a major mitochondrial protein regulating metabolism and apoptosis, the voltage-dependent anion channel 1 (VDAC1), was linked to chemoresistance when in a truncated (VDAC1-ΔC) but active form. The formation of truncated VDAC1, which had a similar channel activity and voltage dependency as full-length, was hypoxia-inducible factor-1 (HIF-1)-dependent and could be inhibited in the presence of the tetracycline antibiotics doxycycline and minocycline, known inhibitors of metalloproteases. Its formation was also reversible upon cell reoxygenation and associated with cell survival through binding to the antiapoptotic protein hexokinase. Hypoxic cells containing VDAC1-ΔC were less sensitive to staurosporine- and etoposide-induced cell death, and silencing of VDAC1-ΔC or treatment with the tetracycline antibiotics restored sensitivity. Clinically, VDAC1-ΔC was detected in tumor tissues of patients with lung adenocarcinomas and was found more frequently in large and late-stage tumors. Together, our findings show that via induction of VDAC1-ΔC, HIF-1 confers selective protection from apoptosis that allows maintenance of ATP and cell survival in hypoxia. VDAC1-ΔC may also hold promise as a biomarker for tumor progression in chemotherapy-resistant patients.

Selective Toxicity of a Quinoxaline 1,4-Di-N-oxide Derivative in Human Tumour Cell Lines

The presence of hypoxic cells in human solid tumours is one of the causes of tumour resistance to conventional therapy, and is also associated with processes that promote the tumour progression. Different chemical agents have been designed in order to take advantage of the particular metabolic characteristics of hypoxic regions. These drugs, called bioreductive agents, are activated inside the hypoxic cells to give active species that, in the presence of oxygen, are oxidised back to the non-toxic parent compound. Several quinoxaline 1,4-di-N-oxides have been described as potential bioreductive agents, and among them, 7-cloro-3-[[(N,N-dimethylamino)propy]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxide hydrocloride (Q-85 HCl) appeared to be the most promising one. In the present work, the selective cytotoxicity of Q-85 HCl was studied in several human tumour cell lines of different origin (Caco2, MCF-7, HT-29 and Tk-10). Cell viability was calculated after 2 h treatment under hypoxic and well-oxygenated conditions. The potency (the concentration that gives 1% of cell survival) in hypoxia and hypoxia cytotoxicity ratio (HCR = potency in oxygenated conditions/potency in hypoxia) were calculated after a 14-day clonogenic assay. Q-85 HCl was more toxic in hypoxia than in well-oxygenated cells in all the tumour cell lines. The best profile of potency in hypoxia (0.4 micromol/L) and selectivity (HCR=155) was found in CaCo-2 cells. Altogether, these results suggest an in vitro biological profile for Q-85 HCl that makes it an interesting candidate for the development as a bioreductive agent.

Prolyl Hydroxylase PHD3 Enhances the Hypoxic Survival and G1 to S Transition of Carcinoma Cells

Hypoxia restricts cell proliferation and cell cycle progression at the G1/S interface but at least a subpopulation of carcinoma cells can escape the restriction. In carcinoma hypoxia may in fact select for cells with enhanced hypoxic survival and increased aggressiveness. The cellular oxygen sensors HIF proline hydroxylases (PHDs) adapt the cellular functions to lowered environmental oxygen tension. PHD3 isoform has shown the strongest hypoxic upregulation among the family members. We detected a strong PHD3 mRNA expression in tumors of head and neck squamous cell carcinoma (HNSCC). The PHD3 expression associated with expression of hypoxic marker gene. Using siRNA in cell lines derived from HNSCC we show that specific inhibition of PHD3 expression in carcinoma cells caused reduced cell survival in hypoxia. The loss of PHD3, but not that of PHD2, led to marked cell number reduction. Although caspase-3 was activated at early hypoxia no induction of apoptosis was detected. However, hypoxic PHD3 inhibition caused a block in cell cycle progression. Cell population in G1 phase was increased and the population in S phase reduced demonstrating a block in G1 to S transition under PHD3 inhibition. In line with this, the level of hyperphosphorylated retinoblastoma protein Rb was reduced by PHD3 knock-down in hypoxia. PHD3 loss led to increase in cyclin-dependent kinase inhibitor p27 expression but not that of p21 or p16. The data demonstrated that increased PHD3 expression under hypoxia enhances cell cycle progression and survival of carcinoma cells.

Adaptation to Survival in Germinal Center Is the Initial Step in Onset of Indolent Stage of Multiple Myeloma

Aberrant mutations of centrocytes in germinal centers (GC) can generate two completely different diseases: B-cell lymphomas and monoclonal gammopathy of undetermined significance (MGUS). In this article we use computational models to examine the evolutionary dynamics by which initial adaptation to survival in the GC allows naive MGUS cells to proliferate in the bone marrow and initiate the evolutionary process that will lead to aggressive multiple myeloma (MM). Our simulations show that MGUS cells may generate bone marrow tumors ranging from indolent to aggressive, depending on the original adaptation in the GC. All these tumors, however, are limited to approximately 15% of the marrow cellularity due to hypoxia-induced quiescence (this correlates with the cellularity that separates MGUS and MM, ∼10%). Resistance to hypoxia-induced quiescence and cell death was one of the two major bone marrow adaptations that allowed continued tumor growth and establishment of paracrine cytokine loops, known to increase MM cell replication and de novo multidrug resistance. The second major adaptation was an increase in IL-6-independent growth rate, which correlates with the mutations observed in advanced stage patients. Even though there was an increase in the microvessel density in all simulations, the "angiogenic switch" was not due to a MM angiogenic phenotype, but rather the response of MM cells to the regional hypoxia caused by the increased tumor burden. These results indicate that treatments targeting the adaptation to survival and proliferation in hypoxia, in conjunction with currently available therapies, may have synergistic effects, by delaying tumor growth and reducing cytokine paracrine loops mediated by angiogenic factors.

FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful reactive oxygen species (ROS). Here, we show that FoxO3A is activated in hypoxia downstream of HIF-1 and mediates the hypoxic repression of a set of nuclear-encoded mitochondrial genes. FoxO3A is required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production and promotes cell survival in hypoxia. FoxO3A is recruited to the promoters of nuclear-encoded mitochondrial genes where it directly antagonizes c-Myc function via a mechanism that does not require binding to the consensus FoxO recognition element. Furthermore, we show that FoxO3A is activated in human hypoxic tumour tissue in vivo and that FoxO3A short-hairpin RNA (shRNA)-expressing xenograft tumours are decreased in size and metabolically changed. Our findings define a novel mechanism by which FoxO3A promotes metabolic adaptation and stress resistance in hypoxia.

Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice

The regulation of neutrophil lifespan by induction of apoptosis is critical for maintaining an effective host response and preventing excessive inflammation. The hypoxia-inducible factor (HIF) oxygen-sensing pathway has a major effect on the susceptibility of neutrophils to apoptosis, with a marked delay in cell death observed under hypoxic conditions. HIF expression and transcriptional activity are regulated by the oxygen-sensitive prolyl hydroxylases (PHD1-3), but the role of PHDs in neutrophil survival is unclear. We examined PHD expression in human neutrophils and found that PHD3 was strongly induced in response to hypoxia and inflammatory stimuli in vitro and in vivo. Using neutrophils from mice deficient in Phd3, we demonstrated a unique role for Phd3 in prolonging neutrophil survival during hypoxia, distinct from other hypoxia-associated changes in neutrophil function and metabolic activity. Moreover, this selective defect in neutrophil survival occurred in the presence of preserved HIF transcriptional activity but was associated with upregulation of the proapoptotic mediator Siva1 and loss of its binding target Bcl-xL. In vivo, using an acute lung injury model, we observed increased levels of neutrophil apoptosis and clearance in Phd3-deficient mice compared with WT controls. We also observed reduced neutrophilic inflammation in an acute mouse model of colitis. These data support what we believe to be a novel function for PHD3 in regulating neutrophil survival in hypoxia and may enable the development of new therapeutics for inflammatory disease.

The neuroglobin expression when retinal ganglion cells death in acute rats' retina ischemia

To investigate the intra-retinal expression of neuroglobin (Ngb) and death of retinal ganglion cells (RGCs) in acute retina ischemia rats. It was an experimental study. The acute retina ischemia model was established by specific hypothesised left retina artery of Sprague-Dawley rats. Forty rats were divided into four groups (0, 15, 30, 60 min) by the time of retina ischemia. Every group has 10 rats, in one group random 3 rats were detected by Western blotting; 4 rats were detected by ganglion cell counted by hematoxylin and eosin stain and immunohistochemistry fluorescence intensity analysis. The rest 3 rats were detected by Western blotting. The difference among different data were analyzed statistically by One-factor analysis of variance and LSD-t analysis. The intra-retinal expression of Ngb reached maximum after acute ischemia 15 minute (P = 0.000). then the expression began decreasing. After 30 minute acute ischemia, the expression of Ngb had approached normal (P = 0.728), while, the cell number of RGCs began lower than 0 min group (P = 0.011); after 60 minute acute ischemia, the expression of Ngb had been obviously lower than 0 min group (P = 0.001), the cell number of RGCs had been further lower than 0 min group (P = 0.000). The expression of Ngb in RGCs layer was highest in rat retina. The expression in inner plexiform layer and external plexiform layer were lower than the former. The expression of Ngb RGCs was mostly intracytoplasm. After 30 minute acute ischemia, the expression of Ngb were detected in mitochondrial outer compartment and mitochondrial cristae, but in cytoplasm of inner nuclear layer and outer nuclear layer the Ngb was not found. Ngb quickly steps-up when RGCs die in acute retina ischemia, and mainly expresses intracytoplasm of RGCs. It has tense relationships with nerve cells' survival in hypoxia.

Abstract 437: A putative role of hypoxia in development of de novo chemoresistance

Abstract In this work we built a computational model that explores the concept of hypoxia induced de novo chemoresistance. We propose that the hypoxic regions of solid tumors not only protect tumor cells from chemotherapy (environmental resistance) but also are the birthplace of de novo multidrug phenotypically chemoresistant cells. These phenotypically resistant cells would be rare in an untreated tumor due to hypoxia and low external pH (pHe) induced quiescence in the environment where they grow. These cells, however, would be subject to a selective pressure for survival by disruption of apoptotic pathways and overexpression of hypoxia-inducible factors which are known to activate multidrug resistance genes, among other pro-survival mechanisms. Tumor cells under chronic hypoxic conditions are also subject to higher genetic instability than tumor cells in normoxia, due in part to the decrease in the expression of homologous recombination proteins, what could also increase the rate of evolution towards a multi-drug chemoresistant phenotype. In the presence of therapy, the sensitive cells (environmentally or phenotypically) are removed from the tumor, reducing hypoxia, normalizing pHe and allowing the phenotypically chemoresistant subpopulation of cells to grow and re-populate the tumor. This work extends our recent chemoresistance model by adding a representation of HIF-1alpha gene, whose response to hypoxia may change due to mutation from varying thresholds until constant activation or deactivation. The expression of this gene is linked to survival in low pHe, expression of multidrug resistance gene (MDR-1) and glycolysis. Our simulations show that HIF-1alpha expression is selected towards constitutive activation due to its increase in glycolysis and low pHe resistance, which in turn increase tumor survival and invasion. Multi-drug resistance is also increased in such cells as a consequence of the selection for these two phenotypes. This work proposes a mechanism for development of chemoresistance in absence of drug which is different from acquired resistance since the selection for this phenotype is not imposed by the drug itself but as side effect of the selection for survival in hypoxia and low pHe. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 437.

Transcriptomic response of rat hippocampus and spleen cells to single and chronic administration of the peptide selank

A new direction in designing new drugs able to effectively reduce anxiety without having side effects is the use of endogenous regulatory peptides. Research� ers of the Institute of Molecular Genetics, Russian Academy of Sciences, and the Zakusov Research Institute of Pharmacology, Russian Academy of Med� ical Sciences, have created the preparation selank, the effective substance of which is a synthetic peptide, an analogue of the short fragment Thr–Lys–Pro–Arg of the heavy chain of human immunoglobulin G, elon� gated at the C terminus with the tripeptide Pro–Gly– Pro. It was shown that selank has a stable nootropic and anxiolytic effects, facilitate brain cell survival in hypoxia, and exhibits an antiviral effect [3, 10].

Antioxidants Improve Early Survival of Cardiomyoblasts After Transplantation to the Myocardium

We tested the hypothesis that modulation of the microenvironment (using antioxidants) will increase stem cell survival in hypoxia and after transplantation to the myocardium. Rat cardiomyoblasts were stably transfected with a reporter gene (firefly luciferase) for bioluminescence imaging (BLI). First, we examined the role of oxidative stress in cells under hypoxic conditions. Subsequently, stem cells were transplanted to the myocardium of rats using high-resolution ultrasound, and their survival was monitored daily using BLI. Under hypoxia, oxidative stress was increased together with decreased cell survival compared to control cells, both of which were preserved by antioxidants. In living subjects, oxidative stress blockade increased early cell survival after transplantation to the myocardium, compared to untreated cells/animals. Modulation of the local microenvironment (with antioxidants) improves stem cell survival. Increased understanding of the interaction between stem cells and their microenvironment will be critical to advance the field of regenerative medicine.

Hypoxia Regulates Insulin Receptor Substrate-2 Expression to Promote Breast Carcinoma Cell Survival and Invasion

Insulin receptor substrate-2 (IRS-2) belongs to the IRS family of adaptor proteins that function as signaling intermediates for growth factor, cytokine, and integrin receptors, many of which have been implicated in cancer. Although the IRS proteins share significant homology, distinct functions have been attributed to each family member in both normal and tumor cells. In cancer, IRS-2 is positively associated with aggressive tumor behavior. In the current study, we show that IRS-2 expression, but not IRS-1 expression, is positively regulated by hypoxia, which selects for tumor cells with increased metastatic potential. We identify IRS-2 as a novel hypoxia-responsive gene and establish that IRS-2 gene transcription increases in a hypoxia-inducible factor-dependent manner in hypoxic environments. IRS-2 is active to mediate insulin-like growth factor I-dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. Functionally, the elevated expression of IRS-2 facilitates breast carcinoma cell survival and invasion in hypoxia. Collectively, our results reveal a novel mechanism by which IRS-2 contributes to the aggressive behavior of hypoxic tumor cells.

Dual role of HIF‐1α in delivering a survival or death signal in hypoxia exposed human K562 erythroleukemia cells

Hypoxia (reduced oxygen tension) is a critical stimulus which switches on a cell rapid response, determining damage and death in some cells, and adaptation and survival in others. Here we report that K562 erythroleukemia cells exposed to hypoxia, proliferated more slowly and the percentage of dead cells increased after 22 h. In parallel HIF (Hypoxia Inducible Factor)-1alpha and Bax level increased, as well as the PKC (Protein Kinase C) delta/Erk (Extracellular Signal Regulated Kinase) pathways being activated. The low level of ROS after 5h of hypoxia did not modify cell cycle progression or affect cell death, whereas HIF-1alpha/CBP (CREB Binding Protein) co-immunoprecipitation and MAPK (Mitogen Activated Protein Kinase)/CREB (c-AMP Response Element Binding) protein signalling pathway activation determined the adaptive survival response. We suggest a dual role for HIF-1alpha in providing a survival or death signal, based on hypoxia duration, and consider the nuclear transcription factor, CREB, to be a possible target for hypoxic therapy against leukemia disease.

Integrated transcriptomic response to cardiac chronic hypoxia: translation regulators and response to stress in cell survival

Complementary deoxyribonucleic acid microarray data from 36 mice subjected for 1, 2, or 4 weeks of their early life to normal atmospheric conditions (normoxia) or chronic intermittent (CIH) or constant (CCH) hypoxia were analyzed to extract organizational principles of the developing heart transcriptome and determine the integrated response to oxygen deprivation. Although both CCH and CIH regulated numerous genes involved in a wide diversity of processes, the changes in maturational profile, expression stability, and coordination were vastly different between the two treatments, indicating the activation of distinct regulatory mechanisms of gene transcription. The analysis focused on the main regulators of translation and response to stress because of their role in the cardiac hypertrophy and cell survival in hypoxia. On average, the expression of each heart gene was tied to the expression of about 20% of other genes in normoxia but to only 8% in CCH and 9% in CIH, indicating a strong decoupling effect of hypoxia. In contrast to the general tendency, the interlinkages among components of the translational machinery and response to stress increased significantly in CIH and much more in CCH, suggesting a coordinated response to the hypoxic stress. Moreover, the transcriptomic networks were profoundly and differently remodeled by CCH and CIH.