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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies of a relatively rare hereditary cancer syndrome, von Hippel-Lindau (VHL) disease, have shed new light on the molecular pathogenesis of kidney cancer and, perhaps more important, on how mammalian cells sense and respond to changes in oxygen availability. This knowledge is already translating into new therapeutic targets for kidney cancer as well as for multiple conditions, such as myocardial infarction and stroke, in which ischemia plays a pathogenic role. This review summarizes the current knowledge of the molecular pathogenesis of von Hippel-Lindau disease and the role of the VHL gene product (pVHL) in kidney cancer and the mammalian oxygen sensing pathway.
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PMID:The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. 1456 79

Although the response of kidneys acutely damaged by ischemia or toxins is dominated by epithelial destruction and regeneration, other studies have begun to define abnormalities in the cell biology of the renal microcirculation, especially with regard to peritubular capillaries. We explored the integrity of peritubular capillaries in relation to expression of vascular endothelial growth factor (VEGF)-A, hypoxia-inducible factor (HIF)-alpha proteins, and von Hippel-Lindau protein (pVHL) in mouse folic acid nephropathy, a model in which acute tubular damage is followed by partial regeneration and progression to patchy chronic histological damage. Throughout a period of 14 days, in areas of cortical tubular atrophy and interstitial fibrosis, loss of VEGFR-2 and platelet endothelial cell adhesion molecule-expressing peritubular capillaries was preceded by marked decreases in VEGF-A transcript and protein levels. Nephrotoxicity was associated with tissue hypoxia, especially in regenerating tubules, as assessed by an established in situ method. Despite the hypoxia, levels of HIF-1 alpha, a protein known to up-regulate VEGF-A, were reduced. During the course of nephrotoxicity, levels of pVHL, a factor that destabilizes HIF-1 alpha, increased significantly. We speculate that that down-regulation of VEGF-A may be functionally-implicated in the progressive attrition of peritubular capillaries in areas of tubular atrophy and interstitial fibrosis; VEGF-A down-regulation correlates with a loss of HIF-1 alpha expression which itself occurs in the face of increased tissue hypoxia.
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PMID:Peritubular capillary loss after mouse acute nephrotoxicity correlates with down-regulation of vascular endothelial growth factor-A and hypoxia-inducible factor-1 alpha. 1463 3

The purpose of this study was to test for the presence of liver hypoxia and recovery after reperfusion when blood alcohol levels (BAL) are high. Male rats were fed ethanol intragastrically at a constant rate for 1 month. The pO(2) levels were then measured on the liver surface of these rats, in vivo during laparatomy under isoflurane anesthesia. To measure the response to acute hypoxia, the hepatic blood flow was clamped off at the porta hepatis. When the clamp was released, recovery from hypoxia was measured. A number of hypoxic-inducible genes in the liver were analyzed by means of quantitative RT-PCR as a measure of increased activation of hypoxia initiated transcription. The mRNA levels of genes for adrenomedullin, adrenergic receptor alpha, 1a and 1d, CDK inhibitor 1a, and erythropoietin were all significantly higher at the peaks than troughs. Expression of these same genes in the livers of control rats fed dextrose was lower than at the troughs. Although the mRNA level of the hypoxia-inducible factor (HIF-1alpha) was higher at the trough than at the peak, its protein concentration in the nuclear fraction was not increased at the troughs compared with the peaks. In fact, the nuclear protein level of HIF-1alpha at the peak was significantly higher than in control samples, which is consistent with the presence of hypoxia at the peaks. Further analysis of the HIF-alpha degradation regulation revealed that prolyl 4-hydroxylase (P4ha1) and von Hippel-Lindau syndrome homolog (Vhl) were both up-regulated at the troughs compared with the peaks. The liver surface oxygen levels at the peaks were reduced compared with the control samples. The pO(2) levels fell abruptly when the vessels at the porta hepatis were clamped. When the clamp was removed, allowing reperfusion of the liver, pO(2) returned to baseline levels in the control, and at the troughs but not at the peaks. These results support the hypothesis that hypoxia occurs at the peaks of the BAL cycle and recovery from ischemia is impaired at the peaks.
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PMID:Liver hypoxia and lack of recovery after reperfusion at high blood alcohol levels in the intragastric feeding model of alcohol liver disease. 1550 34

The putative amino acid sequence of ringed seal (Phoca hispida) hypoxia-inducible factor 1alpha (HIF-1alpha) derived from DNA sequence analysis of the single-copy gene has been investigated. The rationale for these studies was to determine the reasons for the presence of HIF-1alpha at relatively high levels in seal tissues, and its possible role in protection against diving-related oxidative damage. Sequence analysis indicated that the bHLH/PAS and TAD functional domains are very similar to those in terrestrial mammals, although there were significant sequence differences between the mouse and seal proteins in a region of the ODD domain. Some of these results indicate that seal HIF-1alpha protein can bind HIF-Ibeta, DNA, transcriptional coactivators, and von Hippel-Lindau protein (pVHL). The presence of HIF-1alpha in seal tissues was not related to the absence of pVHL, which was found to be present in all seal tissues examined. It is concluded that seal HIF-1alpha may act as a transcriptional activator and that its presence in seal tissues is probably not caused by its inability to interact with pVHL. It is suggested that seal HIF-1 may serve two functions in the postdiving period, namely, to attenuate ischemia/reperfusion-induced oxidative stress and to allow efficient lung reinflation.
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PMID:Hypoxia-inducible factor 1 proteomics and diving adaptations in ringed seal. 1596 12

Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O2 concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O2 and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1alpha hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways--an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.
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PMID:A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1 alpha. 1689 21

The adaptation of animals to oxygen availability is mediated by a transcription factor termed hypoxia-inducible factor (HIF). HIF is an alpha (alpha)/beta (beta) heterodimer that binds hypoxia response elements (HREs) of target genes, including some of medicinal importance, such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). While the concentration of the HIF-beta subunit, a constitutive nuclear protein, does not vary with oxygen availability, the abundance and activity of the HIF-alpha subunits are tightly regulated via oxygen-dependent modification of specific residues. Hydroxylation of prolyl residues (Pro402 and Pro564 in HIF-1alpha) promotes interaction with the von Hippel-Lindau E3 ubiquitin ligase and, consequently, proteolytic destruction by the ubiquitin-proteasome pathway. This prolyl hydroxylation is catalyzed by the prolyl-hydroxylase domain (PHD) containing enzymes for which three isozymes have been identified in humans (1-3). Additionally, asparaginyl hydroxylation (Asn803 in HIF-1alpha) by factor-inhibiting HIF (FIH) ablates interaction of the HIF-alpha subunit with the coactivator p300, providing an alternative mechanism for down-regulation of HIF-dependent genes. Under hypoxic conditions, when oxygen-mediated regulation of the alpha-subunits is curtailed or minimized, dimerization of the alpha- and beta-subunits occurs with subsequent target gene upregulation. Therapeutic activation of HIF signaling has been suggested as a potential treatment for numerous conditions, including ischemia, stroke, heart attack, inflammation, and wounding. One possible route to achieve this is via inhibition of the HIF hydroxylases. This chapter details methods for the purification and assaying of PHD2, the most abundant PHD and the most important in setting steady-state levels of HIF-alpha. Assays are described that measure the activity of PHD2 via direct and indirect means. Furthermore, conditions for the screening of small molecules against PHD2 are described.
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PMID:Hypoxia-inducible factor prolyl-hydroxylase: purification and assays of PHD2. 1799 47

Hypoxia-inducible transcription factor-1alpha and -2alpha (HIF-alpha) proteins and regulated genes are increased in preeclamptic (PE) placentas. Although placental hypoxia likely stabilizes HIF-alpha proteins, we previously reported that there is also a defect in oxygen-dependent reduction of HIF-alpha proteins in PE relative to normal pregnant (NP) placentas that could contribute to their over-expression. After a 4-h exposure to 2% oxygen, placental villous explants were exposed to 21% oxygen over 90 min. As assessed by Western analysis, the defective oxygen-dependent reduction of HIF-1alpha protein in villous explants from PE placenta was unaffected by the protein synthesis inhibitor, cycloheximide. However, after incubation with the proteasomal inhibitor, clasto-lactacystin, oxygen-dependent reduction of HIF-1alpha protein was markedly and similarly impaired in the villous explants from both normal and PE placentas. Thus, impairment of protein degradation rather than increased synthesis causes inadequate oxygen-dependent reduction of HIF-1alpha protein in PE placentas. Immunoprecipitation studies revealed comparable association of HIF-1alpha with von Hippel Lindau (VHL) protein in placentas from NP and PE women. Furthermore, prolyl hydroxylase-3 protein was appropriately upregulated in the PE placentas as determined by Western analysis paralleling the increases of HIF-alpha proteins. These results suggest that molecular events leading to the formation of the HIF-1alpha:VHL:ubiquitin ligase complex are most likely not impaired in PE placentas. Finally, proteasomal trypsin, chymotrypsin, and peptidyl glutamyl-like activities were significantly reduced by approximately 1/3 in PE placentas by using specific peptide substrates coupled to a fluorescent tag. Unexpectedly, however, they were even further decreased in placentas from normotensive women delivering growth restricted babies >37 weeks gestation-placentas which do not have elevated HIF-alpha proteins. In conclusion, accumulation of HIF-alpha proteins in PE placentas may occur as a consequence of both increased formation secondary to relative ischemia/hypoxia and reduced degradation after reperfusion/oxygenation consequent to proteasomal dysfunction. In contrast, in placentas from normotensive women delivering growth restricted babies >37 weeks gestation, proteasomal activity, albeit markedly reduced, is adequate to cope with degradation of HIF-alpha proteins, which have not been increased by an hypoxic environment.
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PMID:Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: implications for expression of HIF-alpha proteins. 1822 38

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-alpha conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) pathway is also activated after IRI and has opposing effects to those promoted by p53. The balance between the HIF-1 and p53 responses can determine the outcome of IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway in a rodent model of IRI. HIF-1alpha is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-alpha increases the faint expression of HIF-1alpha in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1alpha expression is decreased in both CT and TAL. HIF-1alpha expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1alpha expression in the PT after IRI. Additionally, pifithrin-alpha prevents the IRI-induced decrease in HIF-1alpha in the CT and TAL. Parallel changes are observed in the HIF-1alpha transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents the dramatic changes in Von Hippel-Lindau protein morphology and expression after IRI. We conclude that activation of p53 after IRI mitigates the concomitant activation of the protective HIF-1 pathway. Modulating the interactions between the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.
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PMID:p53 regulates renal expression of HIF-1{alpha} and pVHL under physiological conditions and after ischemia-reperfusion injury. 1881 19

Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee. We investigated a potential molecular mechanism underlying a CAPE-mediated protective effect against ischemia/reperfusion (I/R) injury and analyzed the structure contributing to the CAPE effect. CAPE induced hypoxia-inducible factor-1 (HIF-1) alpha protein, concomitantly transactivating the HIF-1 target genes vascular endothelial growth factor and heme oxygenase-1, which play a protective role in I/R injury. CAPE delayed the degradation of HIF-1alpha protein in cells, which occurred by inhibition of HIF prolyl hydroxylase (HPH), the key enzyme for von Hippel-Lindau-dependent HIF-1alpha degradation. CAPE inhibition of HPH and induction of HIF-1alpha protein were neutralized by an elevated dose of iron. The catechol moiety, a chelating group, is essential for HPH inhibition, while hydrogenation of the double bond (-C=C-) in the Michael reaction acceptor markedly reduced potency. Removal of the phenethyl moiety of CAPE (substitution with the methyl moiety) severely deteriorated its inhibitory activity for HPH. Our data suggest that a beneficial effect of CAPE on I/R injury may be ascribed to the activation of HIF-1 pathway via inhibition of HPH and reveal that the chelating moiety of CAPE acted as a pharmacophore while the double bond and phenethyl moiety assisted in inhibiting HPH.
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PMID:Caffeic acid phenethyl ester is a potent inhibitor of HIF prolyl hydroxylase: structural analysis and pharmacological implication. 1974 Jun 41

Vascular/parenchymal crosstalk is increasingly recognized as important in the development and maintenance of healthy vascularized tissues. The retina is an excellent model in which to study the role of cell type-specific contributions to the process of blood vessel and neuronal growth. During retinal vascular development, glial cells such as astrocytes provide the template over which endothelial cells migrate to form the retinal vascular network, and hypoxia-regulated vascular endothelial growth factor (VEGF) has been demonstrated to play a critical role in this process as well as pathological neovascularization. To investigate the nature of cell-specific contributions to this process, we deleted VEGF and its upstream regulators, the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha, and the negative regulator of HIF alpha, von Hippel-Lindau protein (VHL), in astrocytes. We found that loss of hypoxic response and VEGF production in astrocytes does not impair normal development of retinal vasculature, indicating that astrocyte-derived VEGF is not essential for this process. In contrast, using a model of oxygen-induced ischemic retinopathy, we show that astrocyte-derived VEGF is essential for hypoxia-induced neovascularization. Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization.
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PMID:Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. 2054 53


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