Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo.
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ABSTRACT:
SUBMITTER: Kim WY
PROVIDER: S-EPMC1589988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment.We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy.Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.
| S-EPMC2971656 | biostudies-literature
Project description:The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD's activity.
| S-EPMC10003257 | biostudies-literature
Project description:Alcoholic fatty liver disease (AFLD) is a growing health problem for which no targeted therapy is available. We set out to study whether systemic inactivation of the main hypoxia-inducible factor prolyl 4-hydroxylase, HIF-P4H-2 (PHD2/EglN1), whose inactivation has been associated with protection against metabolic dysfunction, could ameliorate it. HIF-P4H-2-deficient and wild-type (WT) mice or HIF-P4H inhibitor-treated WT mice were subjected to an ethanol diet for 3-4 weeks and their metabolic health, liver and white adipose tissue (WAT) were analyzed. Primary hepatocytes from the mice were used to study cellular ethanol metabolism. The HIF-P4H-2-deficient mice retained a healthier metabolic profile, including less adiposity, better lipoprotein profile and restored insulin sensitivity, while on the ethanol diet than the WT. They also demonstrated protection from alcohol-induced steatosis and liver damage and had less WAT inflammation. In liver and WAT the expression of the key lipogenic and adipocytokine mRNAs, such as Fas and Ccl2, were downregulated, respectively. The upregulation of metabolic and antioxidant hypoxia-inducible factor (HIF) target genes, such as Slcs 16a1 and 16a3 and Gclc, respectively, and a higher catalytic activity of ALDH2 in the HIF-P4H-2-deficient hepatocytes improved handling of the toxic ethanol metabolites and oxidative stress. Pharmacological HIF-P4H inhibition in the WT mice phenocopied the protection against AFLD. Our data show that global genetic inactivation of HIF-P4H-2 and pharmacological HIF-P4H inhibition can protect mice from alcohol-induced steatosis and liver injury, suggesting that HIF-P4H inhibitors, now in clinical trials for renal anemia, could also be studied in randomized clinical trials for treatment of AFLD.
| S-EPMC6396018 | biostudies-literature
Project description:Objective: This study aimed to explore the global research status, hot topics, and future prospects in the field of the hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) by bibliometric analysis. Methods: The literatures about HIF-PHI were downloaded from the Web of Science Core Collection and Pubmed database from inceptions to January.10th. 2022. The VOSviewer 1.6.18 was used to explore the bibliometric networks and research priorities of HIF-PHI. Results: A total of 409 papers about HIF-PHI were included, involving 1,674 authors from 548 institutions in 43 countries. The number of HIF-PHI literatures showed an upward trend, with steady growth from 2016 to 2020 and rapid growth in 2021. Tadao Akizawa, Masaomi Nangaku and Alexander R Cobitz published the most literatures. The United States, Japan and China contributed the most publications. The three most contributed institutions are Astellas Pharma Inc., the Showa University and Glaxosmithkline. Therapeutic Apheresis and Dialysis, American Journal of Nephrology and Clinical Pharmacology in Drug Development are the most productive journals. The main hot topics of HIF-PHI field are anemia, chronic kidney disease, hif-phi, epoetin and roxadustat. Conclusion: The United States and Japan are dominant in the field of HIF-PHI research. The discovery and clinical application of HIF-PHI is a great boon for patients with renal anemia. However, due to the short clinical application time of HIF-PHI, and its long-term efficacy and safety still need time to prove. In addition, more cooperation should be carried out between European and American countries and Asian countries to better prove the clinical value of HIF-PHI.
| S-EPMC9549679 | biostudies-literature
Project description:High salt induces the expression of transcription factor hypoxia-inducible factor (HIF) 1alpha and its target genes in the renal medulla, which is an important renal adaptive mechanism to high-salt intake. HIF prolyl-hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1alpha. PHD2 is the predominant isoform of PHDs in the kidney and is primarily expressed in the renal medulla. The present study tested the hypothesis that PHD2 responds to high salt and mediates high-salt-induced increase in HIF-1alpha levels in the renal medulla. In normotensive rats, high-salt intake (4% NaCl, 10 days) significantly inhibited PHD2 expressions and enzyme activities in the renal medulla. Renal medullary overexpression of the PHD2 transgene significantly decreased HIF-1alpha levels. PHD2 transgene also blocked high-salt-induced activation of HIF-1alpha target genes heme oxygenase 1 and NO synthase 2 in the renal medulla. In Dahl salt-sensitive hypertensive rats, however, high-salt intake did not inhibit the expression and activities of PHD2 in the renal medulla. Correspondingly, renal medullary HIF-1alpha levels were not upregulated by high-salt intake in these rats. After transfection of PHD2 small hairpin RNA, HIF-1alpha and its target genes were significantly upregulated by high-salt intake in Dahl salt-sensitive rats. Overexpression of PHD2 transgene in the renal medulla impaired renal sodium excretion after salt loading. These data suggest that high-salt intake inhibits PHD2 in the renal medulla, thereby upregulating the HIF-1alpha expression. The lack of PHD-mediated response to high salt may represent a pathogenic mechanism producing salt-sensitive hypertension.
| S-EPMC2897146 | biostudies-literature
Project description:Cellular and physiological responses to changes in dioxygen levels in metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved prolyl residues in the HIF-alpha subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 A resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded beta-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease.
| S-EPMC1502536 | biostudies-literature
Project description:Osteogenic-angiogenic coupling is promoted by the hypoxia-inducible factor 1-alpha (HIF-1?) transcription factor, provoking interest in HIF activation as a therapeutic strategy to improve osteoblast mineralization and treat pathological osteolysis. However, HIF also enhances the bone-resorbing activity of mature osteoclasts. It is therefore essential to determine the full effect(s) of HIF on both the formation and the bone-resorbing function of osteoclasts in order to understand how they might respond to such a strategy. Expression of HIF-1? mRNA and protein increased during osteoclast differentiation from CD14+ monocytic precursors, additionally inducing expression of the HIF-regulated glycolytic enzymes. However, HIF-1? siRNA only moderately affected osteoclast differentiation, accelerating fusion of precursor cells. HIF induction by inhibition of the regulatory prolyl-4-hydroxylase (PHD) enzymes reduced osteoclastogenesis, but was confirmed to enhance bone resorption by mature osteoclasts. Phd2+/- murine osteoclasts also exhibited enhanced bone resorption, associated with increased expression of resorption-associated Acp5, in comparison with wild-type cells from littermate controls. Phd3-/- bone marrow precursors displayed accelerated early fusion, mirroring results with HIF-1? siRNA. In vivo, Phd2+/- and Phd3-/- mice exhibited reduced trabecular bone mass, associated with reduced mineralization by Phd2+/- osteoblasts. These data indicate that HIF predominantly functions as a regulator of osteoclast-mediated bone resorption, with little effect on osteoclast differentiation. Inhibition of HIF might therefore represent an alternative strategy to treat diseases characterized by pathological levels of osteolysis. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
| S-EPMC5518186 | biostudies-literature
Project description:BackgroundAnemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in <30% of anemic HF patients. Erythropoiesis stimulating agents (ESAs) improve symptoms but are associated with increased risk of thromboembolic events in anemic HF patients with CKD. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia. These agents work by stabilizing the HIF complex, thereby stimulating endogenous erythropoietin production. We hypothesized that HIF-PH inhibitors may be associated with reduced risk of cardiovascular outcomes compared with ESAs in anemic HF patients with CKD. Accordingly, we aim to perform the meta-analysis of studies on the efficacy and safety of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD.MethodsThis meta-analysis will include prospective cohort studies and randomized controlled trials on the effect of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be cardiovascular death. The secondary outcomes will be all-cause death, hospitalization for HF, HF symptoms, exercise capacity, health-related quality of life, and hemoglobin levels.DiscussionThis meta-analysis will evaluate the effect of HIF-PH inhibitors in anemic HF patients with CKD, providing evidence regarding the use of HIF-PH inhibitors in these patients.Systematic review registrationINPLASY202230103.
| S-EPMC9518850 | biostudies-literature
Project description:The hypoxia-inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an α/β-heterodimeric transcription factor that regulates the expression of hundreds of genes in a tissue context-dependent manner. The major hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (factor-inhibiting HIF (FIH)). PHD catalysis regulates HIFα levels, and FIH catalysis regulates HIF activity. How differences in HIFα hydroxylation status relate to variations in the induction of specific HIF target gene transcription is unknown. We report studies using small molecule HIF hydroxylase inhibitors that investigate the extent to which HIF target gene expression is induced by PHD or FIH inhibition. The results reveal substantial differences in the role of prolyl and asparaginyl hydroxylation in regulating hypoxia-responsive genes in cells. PHD inhibitors with different structural scaffolds behave similarly. Under the tested conditions, a broad-spectrum 2-oxoglutarate dioxygenase inhibitor is a better mimic of the overall transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in the transcriptional induction of a subset of genes not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.
| S-EPMC5034057 | biostudies-literature
Project description:Hypoxia-inducible factors (HIFs) are critical transcription factors that mediate cell survival during reduced oxygen conditions (hypoxia). At regular oxygen conditions (normoxia), HIF-1alpha and HIF-2alpha are continuously synthesized in cells and degraded via the ubiquitin-proteasome pathway. During hypoxia, these proteins are stabilized and translocate to the nucleus to activate transcription of target genes that enable cell survival at reduced oxygen levels. HIF proteins are tightly regulated via post-translational modifications including phosphorylation, acetylation, prolyl-hydroxylation and ubiquitination. Here we show for the first time that exogenous and endogenous HIF-2alpha are also regulated via the ubiquitin-like modifier small ubiquitin-like modifiers (SUMO). Using mutational analysis, we found that K394, which is situated in the sumoylation consensus site LKEE, is the major SUMO acceptor site in HIF-2alpha. Functionally, sumoylation reduced the transcriptional activity of HIF-2alpha. Similar to HIF-1alpha, HIF-2alpha is regulated by the SUMO protease SENP1. The proteasome inhibitor MG132 strongly stabilized SUMO-2-conjugated HIF-2alpha during hypoxia but did not affect the total level of HIF-2alpha. The ubiquitin E3 ligases von Hippel-Lindau and RNF4 control the levels of sumoylated HIF-2alpha, indicating that sumoylated HIF-2alpha is degraded via SUMO-targeted ubiquitin ligases.
| S-EPMC2847224 | biostudies-literature