Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines.

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.

HIF-1: structure, biology and natural modulators.

Hypoxia-inducible factor 1 (HIF-1), as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment, participates in many physiological and pathological processes in the body, and is closely related to the pathogenesis of many diseases. This review outlines the mechanisms of HIF-1 activation, its signaling pathways, natural inhibitors, and its roles in diseases. This article can provide new insights in the diagnosis and treatment of human diseases, and recent progress on the development of HIF-1 inhibitors.

Bidirectional Crosstalk Between Hypoxia Inducible Factors and Glucocorticoid Signalling in Health and Disease.

Glucocorticoid-induced (GC) and hypoxia-induced transcriptional responses play an important role in tissue homeostasis and in the regulation of cellular responses to stress and inflammation. Evidence exists that there is an important crosstalk between both GC and hypoxia effects. Hypoxia is a pathophysiological condition to which cells respond quickly in order to prevent metabolic shutdown and death. The hypoxia inducible factors (HIFs) are the master regulators of oxygen homeostasis and are responsible for the ability of cells to cope with low oxygen levels. Maladaptive responses of HIFs contribute to a variety of pathological conditions including acute mountain sickness (AMS), inflammation and neonatal hypoxia-induced brain injury. Synthetic GCs which are analogous to the naturally occurring steroid hormones (cortisol in humans, corticosterone in rodents), have been used for decades as anti-inflammatory drugs for treating pathological conditions which are linked to hypoxia (i.e. asthma, ischemic injury). In this review, we investigate the crosstalk between the glucocorticoid receptor (GR), and HIFs. We discuss possible mechanisms by which GR and HIF influence one another, in vitro and in vivo, and the therapeutic effects of GCs on HIF-mediated diseases.

The role of HIF proteins in maintaining the metabolic health of the intervertebral disc.

The physiologically hypoxic intervertebral disc and cartilage rely on the hypoxia-inducible factor (HIF) family of transcription factors to mediate cellular responses to changes in oxygen tension. During homeostatic development, oxygen-dependent prolyl hydroxylases, circadian clock proteins and metabolic intermediates control the activities of HIF1 and HIF2 in these tissues. Mechanistically, HIF1 is the master regulator of glycolytic metabolism and cytosolic lactate levels. In addition, HIF1 regulates mitochondrial metabolism by promoting flux through the tricarboxylic acid cycle, inhibiting downsteam oxidative phosphorylation and controlling mitochondrial health through modulation of the mitophagic pathway. Accumulation of metabolic intermediates from HIF-dependent processes contribute to intracellular pH regulation in the disc and cartilage. Namely, to prevent changes in intracellular pH that could lead to cell death, HIF1 orchestrates a bicarbonate buffering system in the disc, controlled by carbonic anhydrase 9 (CA9) and CA12, sodium bicarbonate cotransporters and an intracellular H+/lactate efflux mechanism. In contrast to HIF1, the role of HIF2 remains elusive; in disorders of the disc and cartilage, its function has been linked to both anabolic and catabolic pathways. The current knowledge of hypoxic cell metabolism and regulation of HIF1 activity provides a strong basis for the development of future therapies designed to repair the degenerative disc.

HIF-1: structure, biology and natural modulators / 中国天然药物

Hypoxia-inducible factor 1 (HIF-1), as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment, participates in many physiological and pathological processes in the body, and is closely related to the pathogenesis of many diseases. This review outlines the mechanisms of HIF-1 activation, its signaling pathways, natural inhibitors, and its roles in diseases. This article can provide new insights in the diagnosis and treatment of human diseases, and recent progress on the development of HIF-1 inhibitors.

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the 10th most frequent human malignancy and is thus a global burden. Despite some progress in diagnosis and therapy, patients' overall survival rate, between 40 and 55%, has stagnated over the last four decades. Since the tumor node metastasis (TNM) system is not precise enough to predict the disease outcome, additive factors for diagnosis, prognosis, prediction and therapy resistance are urgently needed for OSCC. One promising candidate is the hypoxia inducible factor-1 (HIF-1), which functions as an early regulator of tumor aggressiveness and is a key promoter of energy adaptation. Other parameters comprise the composition of the tumor microenvironment, which determines the availability of nutrients and oxygen. In our opinion, these general processes are linked in the pathogenesis of OSCC. Based on this assumption, the review will summarize the major features of the HIF system-induced activities, its target proteins and related pathways of nutrient utilization and metabolism that are essential for the initiation, progression and therapeutic stratification of OSCC.

Hypoxia-inducible factors and obstructive sleep apnea.

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This Review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of antioxidant genes by HIF-2. ROS in turn activate chemoreflex and suppress baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We also discuss how increased ROS generation by HIF-1 contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.

Bidirectional crosstalk between Hypoxia-Inducible Factor and glucocorticoid signalling in zebrafish larvae.

In the last decades in vitro studies highlighted the potential for crosstalk between Hypoxia-Inducible Factor-(HIF) and glucocorticoid-(GC) signalling pathways. However, how this interplay precisely occurs in vivo is still debated. Here, we use zebrafish larvae (Danio rerio) to elucidate how and to what degree hypoxic signalling affects the endogenous glucocorticoid pathway and vice versa, in vivo. Firstly, our results demonstrate that in the presence of upregulated HIF signalling, both glucocorticoid receptor (Gr) responsiveness and endogenous cortisol levels are repressed in 5 days post fertilisation larvae. In addition, despite HIF activity being low at normoxia, our data show that it already impedes both glucocorticoid activity and levels. Secondly, we further analysed the in vivo contribution of glucocorticoids to HIF activity. Interestingly, our results show that both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) play a key role in enhancing it. Finally, we found indications that glucocorticoids promote HIF signalling via multiple routes. Cumulatively, our findings allowed us to suggest a model for how this crosstalk occurs in vivo.

Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma.

Cancer cells rely on mitochondrial functions to regulate key survival and death signals. How cancer cells regulate mitochondrial autophagy (mitophagy) in the tumor microenvironment as well as utilize mitophagy as a survival signal is still not well understood. Here, we elucidate a key survival mechanism of mitochondrial NIX-mediated mitophagy within the hypoxic region of glioblastoma, the most malignant brain tumor. NIX was overexpressed in the pseudopalisading cells that envelop the hypoxic-necrotic regions, and mitochondrial NIX expression was robust in patient-derived glioblastoma tumor tissues and glioblastoma stem cells. NIX was required for hypoxia and oxidative stress-induced mitophagy through NFE2L2/NRF2 transactivation. Silencing NIX impaired mitochondrial reactive oxygen species clearance, cancer stem cell maintenance, and HIF/mTOR/RHEB signaling pathways under hypoxia, resulting in suppression of glioblastoma survival in vitro and in vivo. Clinical significance of these findings was validated by the compelling association between NIX expression and poor outcome for patients with glioblastoma. Taken together, our findings indicate that the NIX-mediated mitophagic pathway may represent a key therapeutic target for solid tumors, including glioblastoma. SIGNIFICANCE: NIX-mediated mitophagy regulates tumor survival in the hypoxic niche of glioblastoma microenvironment, providing a potential therapeutic target for glioblastoma.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5218/F1.large.jpg.

Inflammation and angiogenesis in the corpus luteum.

Angiogenesis is a very important process that helps establish and maintain the normal structure and function of the corpus luteum (CL). Early luteal development can be considered a kind of physiological injury with an inflammatory response; therefore, the inflammatory response may play an important role in the luteal angiogenesis. The inflammatory response is companied by activated leukocytes and their mediators. For luteal tissue, numerous activated leukocytes such as macrophages, neutrophils and eosinophils are present in the early luteal phase and are widely involved in neovascularization. The objective of this review is to describe the role of the inflammatory factors in the angiogenesis and to discuss their mechanism. Knowledge of action and mechanism of these inflammatory factors on angiogenic activity will be beneficial for the understanding of luteal function.

PIN1 transcript variant 2 acts as a long non-coding RNA that controls the HIF-1-driven hypoxic response.

The transcription factor HIF-1 induces the expression of genes that are essential for cell survival and oxygen homeostasis in hypoxic conditions. The prolyl isomerase Pin1 plays a role in the regulation of HIF-1α. However, the mechanism by which Pin1 controls HIF-1α remains controversial. Surprisingly, we here show that a PIN1 transcript downregulates HIF-1α as a long non-coding RNA. Pin1-silencing siRNAs augmented the hypoxia-induced expression of HIF-1α, thereby upregulating the expression of HIF-1 target genes. However, the overexpression of Pin1 protein did not inhibit the hypoxic expression of HIF-1α. Pin1 restoration in Pin1-depleted cells also failed to reverse the induction of HIF-1α by Pin1 knockdown. Unexpectedly, HIF-1α was found to be induced by both siRNAs for PIN1 transcript variants 1/2 and that for PIN1 transcript variants 2/3, indicating that the PIN1 transcript variant 2 (PIN1-v2) is responsible for HIF-1α induction. Mechanistically, PIN1-v2, which is classified as a long non-coding RNA due to early termination of translation, was evaluated to inhibit the transcription of HIF1A gene. In conclusion, PIN1-v2 may function in balancing the HIF-1-driven gene expression under hypoxia.

Oxygen-Glucose Deprivation/Reoxygenation-Induced Barrier Disruption at the Human Blood-Brain Barrier is Partially Mediated Through the HIF-1 Pathway.

The blood-brain barrier (BBB) plays an important role in brain homeostasis. Hypoxia/ischemia constitutes an important stress factor involved in several neurological disorders by inducing the disruption of the BBB, ultimately leading to cerebral edema formation. Yet, our current understanding of the cellular and molecular mechanisms underlying the BBB disruption following cerebral hypoxia/ischemia remains limited. Stem cell-based models of the human BBB present some potentials to address such issues. Yet, such models have not been validated in regard of its ability to respond to hypoxia/ischemia as existing models. In this study, we investigated the cellular response of two iPSC-derived brain microvascular endothelial cell (BMEC) monolayers to respond to oxygen-glucose deprivation (OGD) stress, using two induced pluripotent stem cells (iPSC) lines. iPSC-derived BMECs responded to prolonged (24 h) and acute (6 h) OGD by showing a decrease in the barrier function and a decrease in tight junction complexes. Such iPSC-derived BMECs responded to OGD stress via a partial activation of the HIF-1 pathway, whereas treatment with anti-angiogenic pharmacological inhibitors (sorafenib, sunitinib) during reoxygenation worsened the barrier function. Taken together, our results suggest such models can respond to hypoxia/ischemia similarly to existing in vitro models and support the possible use of this model as a screening platform for identifying novel drug candidates capable to restore the barrier function following hypoxic/ischemic injury.

[Regulation mechanism of HIFs, PPARs and AMPK in hypoxic training-induced reduction of body weight].

Hypoxic exposure activates hypoxia inducible factors (HIFs) to up-regulate the expression of its target genes. These genes encode glucose metabolism related proteins, such as glucose transporters (GLUTs) and glycolysis related enzymes, including lactate dehydrogenase A (LDHA) and aldolase A (ALDA). Therefore, HIFs participate in oxygenolysis of glucose and play an important role in mediating hypoxia response and weight loss. Exercise training influences fatty acid metabolism, insulin sensitivity and body energy balance through activating peroxisome proliferator-activated receptors (PPARs), which plays an active role in losing weight. In addition, hypoxic exposure or exercise training can activate energy sensor 5'-AMP activated protein kinase (AMPK) in cells and promote oxidation of glucose and fatty acid and weight loss. It has been shown that hypoxic training exerts a better effects on controlling weight, compared with either hypoxic exposure or exercise training alone. This paper reviewed synergistic interactions among HIFs, PPARs and AMPK under hypoxic training and proposed possible mechanisms of hypoxic training-induced weight loss via AMPK-HIFs axis or AMPK-PPARs axis, thus providing theoretical guidance for application of hypoxic training in weight control.

Effects of curcumin on hypoxia-inducible factor as a new therapeutic target.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that consists of two subunits, the HIF-1α and HIF-1ß (ARNT). Under hypoxic conditions, HIF-1 is an adaptive system that regulates the transcription of multiple genes associated with growth, angiogenesis, proliferation, glucose transport, metabolism, pH regulation and cell death. However, aberrant HIF-1 activation contributes to the pathophysiology of several human diseases such as cancer, ischemic cardiovascular disorders, and pulmonary and kidney diseases. A growing body of evidence indicates that curcumin, a natural bioactive compound of turmeric root, significantly targets both HIF-1 subunits, but is more potent against HIF-1α. In this review, we have summarized the knowledge about the pharmacological effects of curcumin on HIF-1 and the related molecular mechanisms that may be effective candidates for the development of multi-targeted therapy for several human diseases.

[Is Oxygen Deficiency Always Harmful?] / Ist Sauerstoffmangel immer nur schädlich?

Is Oxygen Deficiency Always Harmful? Abstract. The role of the cardiovascular circulation is to supply tissue with oxygen and nutrients. Oxygen deficiency (hypoxia) is considered life-threatening, since cells die, either through apoptotic or necrotic processes. Tissue tries to counteract this by means of evolutionary signalling pathways, such as the nuclear hypoxia-inducible factor, which protects the tissue by promoting cell survival strategies and simultaneously intervening in angiogenesis, haematogenesis and metabolic processes. Recent findings indicate that these conserved signalling pathways can also function as therapeutic approaches in wound healing of bones and skin, as well as in the regeneration of tissues, e.g. in the liver, and in the hematopoietic system.

Un viaje entre la hipoxia de la gran altitud y la hipoxia del enfermo crítico: ¿qué puede enseñarnos en la compresión y manejo de las enfermedades críticas? / A journey between high altitude hypoxia and critical patient hypoxia: What can it teach us about compression and the management of critical disease?

La hipoxia de la altitud (hipoxia hipobárica) no deja de ser una hipoxia celular similar a la que presentan los enfermos críticos. Estudiar a los alpinistas expuestos a la hipoxia extrema ofrece la ventaja de que es una población relativamente homogénea y sana, en contraste con la población heterogénea y generalmente menos saludable que suele observarse en las Unidades de Cuidados Críticos. El conocimiento de la fisiología y la enfermedad de la altitud abren caminos para comprender en qué medida afecta la hipoxia a los pacientes críticos. Los cambios comparables en la biogénesis mitocondrial entre ambos grupos pueden reflejar respuestas adaptativas similares y sugieren intervenciones terapéuticas basadas en la protección o estimulación de la biogénesis mitocondrial. El predominio del alelo homocigótico de inserción (II) de la enzima de conversión de la angiotensina está presente tanto en las ascensiones exitosas sin oxígeno por encima de los 8.000 m como en la supervivencia de algunas enfermedades de los enfermos críticos

High altitude sickness (hypobaric hypoxia) is a form of cellular hypoxia similar to that suffered by critically ill patients. The study of mountaineers exposed to extreme hypoxia offers the advantage of involving a relatively homogeneous and healthy population compared to those typically found in Intensive Care Units (ICUs), which are heterogeneous and generally less healthy. Knowledge of altitude physiology and pathology allows us to understanding how hypoxia affects critical patients. Comparable changes in mitochondrial biogenesis between both groups may reflect similar adaptive responses and suggest therapeutic interventions based on the protection or stimulation of such mitochondrial biogenesis. Predominance of the homozygous insertion (II) allele of the angiotensin-converting enzyme gene is present in both individuals who perform successful ascensions without oxygen above 8000 m and in critical patients who overcome certain disease conditions

El suero de seno coronario tras un infarto de miocardio induce angiogénesis y reparación de la obstrucción microvascular. Implicación del factor inducible por hipoxia-1A / Coronary serum obtained after myocardial infarction induces angiogenesis and microvascular obstruction repair. Role of hypoxia-inducible factor-1A

Introducción y objetivos: El objetivo es estudiar la angiogénesis coronaria inducida por el suero coronario y la implicación del factor inducible por hipoxia-1A (FIH-1A) en la reparación de la obstrucción microvascular (OMV) tras un infarto agudo de miocardio (IAM). Métodos: Se indujo un IAM en cerdos mediante oclusión coronaria durante 90 min. Se dividió a los animales entre 1 grupo de control y 4 grupos con IAM: sin reperfusión y 1 min, 1 semana y 1 mes tras la reperfusión. Se cuantificaron la OMV y la densidad microvascular. Se determinó la capacidad angiogénica del suero coronario mediante una prueba de tubulogénesis in vitro. Se determinaron las concentraciones circulantes del FIH-1A, su implicación en el miocardio infartado y el efecto del bloqueo del FIH-1A in vitro. Resultados: En la zona infartada, la microvascularización disminuye tras 90 min de isquemia, la OMV aparece tras 1 min de reperfusión, es máxima 1 semana tras la reperfusión y se resuelve en 1 mes. La capacidad angiogénica del suero aumenta durante la isquemia y 1 min tras la reperfusión (32 ± 4 y 41 ± 9 frente a 3 ± 3 tubos en el grupo de control; p < 0,01). Las concentraciones circulantes del FIH-1A se incrementan durante la isquemia (5 min de isquemia: 273 ± 52 frente a 148 ± 48 pg/ml de los controles; p < 0,01) y se hallan en la microvasculatura de todos los grupos con IAM (sin reperfusión frente a control, el 67 ± 5% frente al 15 ± 17%; p < 0,01). El bloqueo del FIH-1A in vitro reduce la capacidad angiogénica inducida por el suero. Conclusiones: El suero coronario activa la neoangiogénesis desde antes de la reperfusión, y el FIH-1A podría tener un papel crucial. La capacidad angiogénica del suero coronario puede contribuir a la comprensión de la fisiopatología tras el IAM

Introduction and objectives: Microvascular obstruction (MVO) exerts deleterious effects following acute myocardial infarction (AMI). We investigated coronary angiogenesis induced by coronary serum and the role of hypoxia-inducible factor-1A (HIF-1A) in MVO repair. Methods: Myocardial infarction was induced in swine by transitory 90-minute coronary occlusion. The pigs were divided into a control group and 4 AMI groups: no reperfusion, 1 minute, 1 week and 1 month after reperfusion. Microvascular obstruction and microvessel density were quantified. The proangiogenic effect of coronary serum drawn from coronary sinus on endothelial cells was evaluated using an in vitro tubulogenesis assay. Circulating and myocardial HIF-1A levels and the effect of in vitro blockade of HIF-1A was assessed. Results: Compared with control myocardium, microvessel density decreased at 90-minute ischemia, and MVO first occurred at 1 minute after reperfusion. Both peaked at 1 week and almost completely resolved at 1 month. Coronary serum exerted a neoangiogenic effect on coronary endothelial cells in vitro, peaking at ischemia and 1 minute postreperfusion (32 ± 4 and 41 ± 9 tubes vs control: 3 ± 3 tubes; P < .01). Hypoxia-inducible factor-1A increased in serum during ischemia (5-minute ischemia: 273 ± 52 pg/mL vs control: 148 ± 48 pg/mL; P < .01) being present on microvessels of all AMI groups (no reperfusion: 67% ± 5% vs control: 15% ± 17%; P < .01). In vitro blockade of HIF-1A reduced the angiogenic response induced by serum. Conclusions: Coronary serum represents a potent neoangiogenic stimulus even before reperfusion; HIF-1A might be crucial. Coronary neoangiogenesis induced by coronary serum can contribute to understanding the pathophysiology of AMI

A journey between high altitude hypoxia and critical patient hypoxia: What can it teach us about compression and the management of critical disease? / Un viaje entre la hipoxia de la gran altitud y la hipoxia del enfermo crítico: ¿qué puede enseñarnos en la compresión y manejo de las enfermedades críticas?

High altitude sickness (hypobaric hypoxia) is a form of cellular hypoxia similar to that suffered by critically ill patients. The study of mountaineers exposed to extreme hypoxia offers the advantage of involving a relatively homogeneous and healthy population compared to those typically found in Intensive Care Units (ICUs), which are heterogeneous and generally less healthy. Knowledge of altitude physiology and pathology allows us to understanding how hypoxia affects critical patients. Comparable changes in mitochondrial biogenesis between both groups may reflect similar adaptive responses and suggest therapeutic interventions based on the protection or stimulation of such mitochondrial biogenesis. Predominance of the homozygous insertion (II) allele of the angiotensin-converting enzyme gene is present in both individuals who perform successful ascensions without oxygen above 8000 m and in critical patients who overcome certain disease conditions.

Angelica sinensis Exerts Angiogenic and Anti-apoptotic Effects Against Cerebral Ischemia-Reperfusion Injury by Activating p38MAPK/HIF-1[Formula: see text]/VEGF-A Signaling in Rats.

This study evaluated the effects of Angelica sinensis extract [Dang Gui (DG)] administered before 60[Formula: see text]min of middle cerebral artery occlusion followed by 3[Formula: see text]d of reperfusion and investigated the involvement of mitogen-activated protein kinase (MAPK)/hypoxia-inducible factor (HIF)-1[Formula: see text] signaling in the cortical ischemic penumbra. DG was intraperitoneally administered at a dose of 0.25[Formula: see text]g/kg (DG-0.25g), 0.5[Formula: see text]g/kg (DG-0.5g), or 1[Formula: see text]g/kg (DG-1g) 30[Formula: see text]min before the onset of cerebral ischemia. Our study results revealed that DG-0.5g and DG-1g pretreatment effectively attenuated cerebral infarct and improved neurological deficits. DG-0.5g and DG-1g pretreatment significantly downregulated glial fibrillary acidic protein (GFAP), cytochrome c, and cleaved caspase-3 expression and upregulated phospho-p38 MAPK (p-p38 MAPK)/p38 MAPK, phospho-cAMP response element-binding protein (p-CREB)/CREB, cytosolic and mitochondrial phospho-Bad (p-Bad)/Bad ratios, and HIF-1[Formula: see text], vascular endothelial growth factor-A (VEGF-A), phospho-90 kDa ribosomal S6 kinase (p-p90RSK), and von Willebrand factor (vWF) expression in the cortical ischemic penumbra. Pretreatment with SB203580, a p38 MAPK inhibitor, dramatically abrogated the upregulating effects of DG-1g on p-p38 MAPK/p38 MAPK, p-CREB/CREB, and p-Bad/Bad ratios and HIF-1[Formula: see text], VEGF-A, and vWF expression and the downregulating effects of DG-1g on GFAP, cytochrome c, cleaved caspase-3, and cerebral infarction. DG-0.5g and DG-1g pretreatment provided neuroprotective effects against astrocyte-mediated cerebral infarction by activating angiogenic and anti-apoptotic signaling. Moreover, the angiogenic and anti-apoptotic effects of DG pretreatment can be attributed to the activation of p38 MAPK/HIF-1[Formula: see text]/VEGF-A/vWF signaling and p38 MAPK/HIF-1[Formula: see text]/VEGF-A/p-Bad-related regulation of cytochrome c/caspase-3 signaling, respectively, in the cortical ischemic penumbra 3[Formula: see text]d after reperfusion.

Epithelial Barrier Regulation by Hypoxia-Inducible Factor.

Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and the lung are lined by layer(s) of epithelial cells that, when organized in three dimensions, provide a critical barrier to the flux of luminal contents. This selective barrier is provided through the regulated expression of junctional proteins and mucins. Tissue oxygen metabolism is central to the maintenance of homeostasis in the mucosa. In some organs (e.g., the colon), low baseline Po2 determines tissue metabolism and results in basal expression of the transcription factor, hypoxia-inducible factor (HIF), which is enhanced after ischemia/inflammation. Recent studies have indicated that HIF contributes fundamentally to the expression of barrier-related genes and in the regulation of barrier-adaptive responses within the mucosa. Here, we briefly review recent literature on the topic of hypoxia and HIF regulation of barrier in mucosal health and during disease.