Association of rs11549465 (C1772T) variant of hypoxia-inducible factor-1α with Covid-19 susceptibility. A population-based epidemiological study.
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ABSTRACT:
SUBMITTER: Das A
PROVIDER: S-EPMC8382105 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
Association of rs11549465 (C1772T) variant of hypoxia-inducible factor-1α with Covid-19 susceptibility. A population-based epidemiological study.
Das Anamika A Patra Maheswari M Dhangadamajhi Gunanidhi G
Human cell 20210823 6
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Project description:BackgroundA meta-analysis was performed to estimate the association between HIF-1α polymorphism (C1772T) and breast cancer risk.Material and methodsThe relevant published literature was retrieved from PubMed, Web of Knowledge, and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations.ResultsSix case-control studies, including 2043 cases and 2146 controls were identified. Meta-analysis showed that there was no marked association between C1772T polymorphism and breast cancer risk in the overall population in the dominant model. The subgroup analysis showed an increased breast cancer risk in Asians based on homozygote comparison and the recessive model. There were no associations between C1772T polymorphism with clinicopathological parameters and habits.ConclusionsThe present meta-analysis suggests that HIF-1α C1772T polymorphism is a risk factor for susceptibility to breast cancer in Asians.
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Project description:ObjectiveThis meta-analysis was implemented to evaluate the association between hypoxia-inducible factor-1α (HIF-1α) C1772T/G1790A polymorphisms and susceptibility to head and neck cancer (HNC).Material and methodsThis meta-analysis has been registered on PROSPERO platform ( CRD42021257309 ). The PubMed, Embase and Web of Science databases were searched to retrieve eligible published papers. STATA software was used to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the correlation strength.ResultsOur results demonstrated that the HIF-1α C1772T polymorphism was significantly related to an increased HNC risk (OR = 2.27, 95% CI = 1.17-4.42 for the homozygous model; OR = 11.53, 95% CI = 1.11-120.4 for the recessive model), especially in Caucasians (OR = 2.16, 95% CI = 1.09-4.27 for the homozygous model; OR = 2.28, 95% CI = 1.15-5.51 for the recessive model). Similarly, a remarkable correlation was discovered between the G1790A polymorphism and HNC risk (OR = 72.11, 95% CI = 2.08-2502.4 for the homozygous model; OR = 58.05, 95% CI = 1.70-1985.77 for the recessive model). Moreover, in the subgroup analysis by source of controls, a statistically significant correlation was discovered in the population-based (PB) subgroup (OR = 9.43, 95% CI = 1.20-73.9 for allelic model; OR = 72.11, 95% CI = 2.08-2502.4 for the homozygous model; OR = 3.22, 95% CI = 1.28-8.08 for the heterozygous model; OR = 7.83, 95% CI = 1.48-41.37 for the dominant model; OR = 58.05, 95% CI = 1.70-1985.8 for the recessive model) but not in the hospital-based (HB) subgroup.ConclusionOur study found that both HIF-1α C1772T and G1790A polymorphisms might be a higher risk of HNC, especially in the Caucasian group with the C1772T polymorphism.
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Project description:The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.
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Project description:Hypoxia-inducible factors (HIFs) are key transcriptional mediators of the hypoxic response and are implicated in oncogenesis. HIFα is regulated by a well-characterized, oxygen-dependent degradation pathway involving the von Hippel Lindau (VHL) tumor suppressor protein. However, comparatively little is known about HIFα regulation at the translational level, particularly under cellular stress. There is evidence that HIFα expression not only responds to changes in oxygen tension, but also nutrient availability. In this study, we monitored global translation rates, ATP levels and HIF1α synthesis rates in response to glucose starvation or glycolysis inhibition. We found that both global and HIF1α-specific translation rates decline under glucose deprivation that is concomitant with ATP reduction. These results are in contrast with previous reports showing preferential HIF1α synthesis despite global translation suppression under hypoxia and suggest that a glucose requirement in cellular metabolism is associated with HIF1α translation.
| S-EPMC11519269 | biostudies-literature
Project description:A proper cellular adaptation to low oxygen levels is essential for processes such as development, growth, metabolism, and angiogenesis. The response to decrease in oxygen supply, referred to as hypoxia, is also involved in numerous human diseases including cancer, inflammatory conditions, and vascular disease. The hypoxia-inducible factor 1-α (HIF-1α), a key player in the hypoxic response, is kept under stringent regulation. At normoxia, the levels are kept low as a consequence of the efficient degradation by the ubiquitin-proteasome system, and in response to hypoxia, the degradation is blocked and the accumulating HIF-1α promotes a transcriptional response essential for proper adaptation and survival. Here we show that the ubiquitin-specific protease-19 (USP19) interacts with components of the hypoxia pathway including HIF-1α and rescues it from degradation independent of its catalytic activity. In the absence of USP19, cells fail to mount an appropriate response to hypoxia, indicating an important role for this enzyme in normal or pathological conditions.
| S-EPMC3265877 | biostudies-literature
Project description:The stabilisation of HIF-α is central to the transcriptional response of animals to hypoxia, regulating the expression of hundreds of genes including those involved in angiogenesis, metabolism and metastasis. HIF-α is degraded under normoxic conditions by proline hydroxylation, which allows for recognition and ubiquitination by the von-Hippel-Lindau (VHL) E3 ligase complex. The aim of our study was to investigate the posttranslational modification of HIF-1α in tumours, to assess whether there are additional mechanisms besides reduced hydroxylation leading to stability. To this end we optimised antibodies against the proline-hydroxylated forms of HIF-1α for use in formalin fixed paraffin embedded (FFPE) immunohistochemistry to assess effects in tumour cells in vivo. We found that HIF-1α proline-hydroxylated at both VHL binding sites (Pro402 and Pro564), was present in hypoxic regions of a wide range of tumours, tumour xenografts and in moderately hypoxic cells in vitro. Staining for hydroxylated HIF-1α can identify a subset of breast cancer patients with poorer prognosis and may be a better marker than total HIF-1α levels. The expression of unhydroxylated HIF-1α positively correlates with VHL in breast cancer suggesting that VHL may be rate-limiting for HIF degradation. Our conclusions are that the degradation of proline-hydroxylated HIF-1α may be rate-limited in tumours and therefore provides new insights into mechanisms of HIF upregulation. Persistence of proline-hydroxylated HIF-1α in perinecrotic areas suggests there is adequate oxygen to support prolyl hydroxylase domain (PHD) activity and proline-hydroxylated HIF-1α may be the predominant form associated with the poorer prognosis that higher levels of HIF-1α confer.
| S-EPMC3923075 | biostudies-literature
Project description:The receptor-tyrosine kinase ErbB4 was identified as a direct regulator of hypoxia-inducible factor-1α (HIF-1α) signaling. Cleaved intracellular domain of ErbB4 directly interacted with HIF-1α in the nucleus, and stabilized HIF-1α protein in both normoxic and hypoxic conditions by blocking its proteasomal degradation. The mechanism of HIF stabilization was independent of VHL and proline hydroxylation but dependent on RACK1. ErbB4 activity was necessary for efficient HRE-driven promoter activity, transcription of known HIF-1α target genes, and survival of mammary carcinoma cells in vitro. In addition, mammary epithelial specific targeting of Erbb4 in the mouse significantly reduced the amount of HIF-1α protein in vivo. ERBB4 expression also correlated with the expression of HIF-regulated genes in a series of 4552 human normal and cancer tissue samples. These data demonstrate that soluble ErbB4 intracellular domain promotes HIF-1α stability and signaling via a novel mechanism.
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Project description:Mesenchymal stem cells (MSCs) are ideal materials for cell therapy. Research has indicated that hypoxia benefits MSC survival, but little is known about the underlying mechanism. This study aims to uncover potential mechanisms involving hypoxia inducible factor 1α (HIF1A) to explain the promoted MSC survival under hypoxia. MSCs were obtained from Sprague-Dawley rats and cultured under normoxia or hypoxia condition. The overexpression vector or small interfering RNA of Hif1a gene was transfected to MSCs, after which cell viability, apoptosis and expression of HIF1A were analyzed by MTT assay, flow cytometry, qRT-PCR and Western blot. Factors in p53 pathway were detected to reveal the related mechanisms. Results showed that hypoxia elevated MSCs viability and up-regulated HIF1A (P < 0.05) as previously reported. HIF1A overexpression promoted viability (P < 0.01) and suppressed apoptosis (P < 0.001) under normoxia. Correspondingly, HIF1A knockdown inhibited viability (P < 0.05) and promoted apoptosis (P < 0.01) of MSCs under hypoxia. Expression analysis suggested that p53, phosphate-p53 and p21 were repressed by HIF1A overexpression and promoted by HIF1A knockdown, and B-cell CLL/lymphoma 2 (BCL2) expression had the opposite pattern (P < 0.05). These results suggest that HIF1A may improve viability and suppress apoptosis of MSCs, implying the protective effect of HIF1A on MSC survival under hypoxia. The underlying mechanisms may involve the HIF1A-suppressed p53 pathway. This study helps to explain the mechanism of MSC survival under hypoxia, and facilitates the application of MSCs in cell therapy.
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Project description:Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1α (HIF-1α). HIF-1α and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1α expression and autophagy in rat and mouse models of PKD. HIF-1α was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112-day-old Pkd2WS25/- mice with a mutation in the Pkd2 gene were studied. HIF-1α was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/- kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1α. To determine the role of HIF-1α in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1α is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1α did not have a therapeutic effect.
| S-EPMC3094047 | biostudies-literature