Muscle Ring Finger-1 regulation of right-sided heart transcriptional responses to hypoxia in vivo.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE82345 | GEO | 2018/08/24
REPOSITORIES: GEO
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Project description:We previously identified a role for the muscle-specific ubiquitin ligase MuRF1 (Muscle Ring Finger-1) in cardiac ischemia-reperfusion (I/R) injury. We found that cardiomyocyte-specific (alphaMHC-) MuRF1 transgenic mice (MuRF1 Tg+) mice were significantly protected from I/R injury. As we discovered MuRF1’s regulation of other transcriptions factors, we sought to identify other ways in which MuRF1 was cardioprotective in I/R injury. In the present study, we first identified the regulation of MuRF1 expression by qPCR in a porcine model of I/R injury. MuRF1 mRNA significantly increased within 90 minutes of I/R injury. We next assayed MuRF1 Tg+ ventricular tissue after I/R reperfusion injury by microarray (44K transcripts) to identify how MuRF1 regulates the transcriptome. We identified 71 significantly altered genes having a >1.5-fold (p<0.01) in MuRF1 Tg+ and wildtype hearts challenged with I/R injury (or sham operation). Functional annotation of the top upregulated genes found enrichment for myogenesis, cell adhesion, and nucleic acid metabolism. TRANSFAC analysis of MuRF1 Tg+ significant genes identified enrichment for genes (30-53%) with promoter regions recognized by the transcription factors MAZ, PIT1, VMW65, and BACH2. The transcription factor MAZ binds muscle creatine kinase (MCK) promoter in skeletal and cardiac myocytes, known most for its regulation of myogenin and MEF2C in cardiomyocytes. While the role of PIT1 and BACH2 in adult cardiomyocytes is not clear, VMW65 is a powerful transactivator with functions in chromatin remodeling. In neonatal cardiomycoyte I/R injury, VMW65 associates with HIF1alpha to upregulate cardioprotective VEGF, Glut-1, Glut-4, HSP70, and iNOS expression. These findings elucidate the MuRF1-specific regulation of genes in cardiac I/R injury that are associated with cardioprotection and may represent multiple additional direct or indirect mechanisms that MuRF1 regulates cardiomyocyte signaling.
2019-01-05 | GSE108940 | GEO
Project description:To identify the effects of hypoxia on stem cell populations, we subjected human mesenchymal stem cells to a pO2 of 4 mmHg and analyzed global gene expression and alternative splicing (AS) by genome-exon microarray. Hypoxia induced gene expression in human mesenchymal stem cells was measured at 24 hours after exposure to 0.5% oxygen or normal 21% oxygen. Three independent experiments were performed per condition (Hypoxia or Normoxia).
2014-03-14 | E-GEOD-55875 | biostudies-arrayexpress
Project description:Rationale: MicroRNAs play key roles in hypertrophic stress responses. miR-378(-3p) is a highly abundant, cardiomyocyte-enriched microRNA whose downregulation in pressure-overload has been suggested as detrimental to the heart. Previous studies have utilized systemic anti-miR or microRNA-encoding virus administration, and thus questions regarding the cardiomyocyte-autonomous roles of miR-378 remain. Objective: To examine whether persistent overexpression of miR-378 in cardiomyocytes alters the phenotype of the unstressed heart, whether its overexpression is beneficial or deleterious in the setting of pressure-overload, and to comprehensively identify its cardiomyocyte-specific effects on mRNA regulation. Methods and Results: Cardiac function was compared in young (10-12 week-old) mice overexpressing miR-378 in the heart under the control of the Myh6 promoter (alphaMHC-miR-378 mice), in older (40 week-old) mice and their age-matched wild-type controls. Older alphaMHC-miR-378 mice exhibited decreased fractional shortening and modest chamber dilation with an increase in cardiomyocyte length. When subjected to pressure-overload, cardiomyocyte length was increased in young alphaMHC-miR-378 mice, but fractional shortening declined precipitously over two weeks. Transcriptome profiling of wild-type and alphaMHC-miR-378 hearts in unstressed and pressure-overload conditions revealed dysregulation of several upstream metabolic and mitochondrial genes in alphaMHC-miR-378 hearts, compromising the reprogramming that occurs during early adaptation to pressure overload. Ago2 immunoprecipitation with mRNA sequencing revealed novel miR-378 cardiac mRNA targets including Akt1 and Epac2 and demonstrated the contextual nature of previously described miR-378 targeting events. Conclusions: Long-term upregulation of miR-378 levels in the heart is not innocuous and exacerbates contractile dysfunction in pressure-overload hypertrophy through numerous signaling mechanisms.
2015-09-30 | GSE61734 | GEO
Project description:We investigated the role of cardiomyocyte MuRF1 in the transcriptional responses to cyclic stretch (15% biaxial stretch at 1 Hz for 60 min) using the HL-1 cell line.
2021-08-10 | GSE118229 | GEO
Project description:After gastrulation, oviductal hypoxia maintains turtle embryos in an arrested state prior to oviposition. Subsequent exposure to atmospheric oxygen upon oviposition initiates recommencement of embryonic development. Arrest can be artificially extended for several days after oviposition by incubation of the egg under hypoxic conditions, with development recommencing in an apparently normal fashion after subsequent exposure to normoxia. To examine the transcriptomic events associated with embryonic arrestAfter gastrulation, oviductal hypoxia maintains turtle embryos in an arrested state prior to oviposition. Subsequent exposure to atmospheric oxygen upon oviposition initiates recommencement of embryonic development. Arrest can be artificially extended for several days after oviposition by incubation of the egg under hypoxic conditions, with development recommencing in an apparently normal fashion after subsequent exposure to normoxia. To examine the transcriptomic events associated with embryonic arrest, RNA-sequencing analysis was performed on embryos from freshly laid eggs and eggs incubated in either normoxia (oxygen tension ~159 mmHg) or hypoxia (<8 mmHg) for 36 hours (h) after oviposition (n = 5 per group). The patterns of gene expression differed markedly among the three experimental groups. Normal embryonic development in normoxia was associated with up-regulation of genes involved in DNA replication, the cell cycle, and mitosis, but these genes were commonly down-regulated after incubation in hypoxia. Many target genes of hypoxia inducible factors, including insulin-like growth factor binding protein 1, were down-regulated by normoxic incubation but upregulated by incubation in hypoxia. Notably, some of the transcriptomic effects of hypoxia in green turtle embryos resembled those reported by others to be associated with hypoxia-induced embryonic arrest in diverse taxa, including budding yeast (Saccharomyces cerevisiae), the annelid Caenorhabditis elegans, and zebrafish (Danio rerio). Thus, while among oviparous species, hypoxia-induced pre-ovipositional embryonic arrest appears to be a unique adaptation of turtles, mechanisms underlying hypoxia-induced embryonic arrest per se may be highly conserved across the diverse taxa in which this mechanism operates. We report the transciptional changes in Chelonia mydas embryos incubated in either normoxia or hypoxia comapred to freshly laid eggs.
2022-05-31 | GSE197628 | GEO
Project description:This series compares the effects that two pharmacologically distinct ligands at the mitochondrial peripheral-type benzodiazepine receptor (Bzrp) has on gene expression in early mouse embryos cultured under different oxygen levels. Mouse embryos averaging 16-18 somite pairs were explanted on 9 d.p.c. and grown in culture under optimal oxygenation (21% oxygen, hyperbaric with respect to arterial blood = 80-100 mmHg). Most embryos (>90%) develop normally in over a 24h culture period. When embryos receive suboptimal oxygenation for 2.0h (5% oxygen, similar to venous blood = 38-40 mmHg) a high percentage of them (>60%) go on to develop abnormally or else fail. These hypoxic embryos are remediated with 5 uM PK11195 to ~25% malformation rate. Cultured embryos were exposed to different oxygen levels (5% or 21%) in the presence of the Bzrp ligands PK11195 (Bzrp antagonist) versus Ro5-4864 (Bzrp agonist). The sampling time was guided by p53 protein induction with hypoxia, and remediation with PK11195, at 4.0h of culture and exposures. Thus all measurements were on RNA from the prosencephalon collected 2.0h after start of the test period on 9 d.p.c. Keywords = peripheral benzodiazepine receptor Keywords = oxygen sensing Keywords = Bzrp ligands Keywords = PK11195 Keywords = Ro5-4864 Keywords = embryo Keywords = p53 protein induction
2010-06-09 | E-GEOD-1079 | biostudies-arrayexpress
Project description:Interventions: Group 1:neuromuscular monitoring, TOF=0,PTC=1-2,pneumoperitoneal pressure 12 mmHg;regular neuromuscular blockade:neuromuscular monitoring, TOF=1-2, pneumoperitoneal pressure 15 mmHg
Primary outcome(s): cerebral oxygen saturation;tissue oxygen saturation;S100B protein
Study Design: Parallel
| 39594 | ecrin-mdr-crc
Project description:This series compares the effects that two pharmacologically distinct ligands at the mitochondrial peripheral-type benzodiazepine receptor (Bzrp) has on gene expression in early mouse embryos cultured under different oxygen levels. Mouse embryos averaging 16-18 somite pairs were explanted on 9 d.p.c. and grown in culture under optimal oxygenation (21% oxygen, hyperbaric with respect to arterial blood = 80-100 mmHg). Most embryos (>90%) develop normally in over a 24h culture period. When embryos receive suboptimal oxygenation for 2.0h (5% oxygen, similar to venous blood = 38-40 mmHg) a high percentage of them (>60%) go on to develop abnormally or else fail. These hypoxic embryos are remediated with 5 uM PK11195 to ~25% malformation rate. Cultured embryos were exposed to different oxygen levels (5% or 21%) in the presence of the Bzrp ligands PK11195 (Bzrp antagonist) versus Ro5-4864 (Bzrp agonist). The sampling time was guided by p53 protein induction with hypoxia, and remediation with PK11195, at 4.0h of culture and exposures. Thus all measurements were on RNA from the prosencephalon collected 2.0h after start of the test period on 9 d.p.c. Keywords = peripheral benzodiazepine receptor Keywords = oxygen sensing Keywords = Bzrp ligands Keywords = PK11195 Keywords = Ro5-4864 Keywords = embryo Keywords = p53 protein induction Keywords: ordered
2004-03-11 | GSE1079 | GEO
Project description:Heart disease remains the leading cause of death globally. Although reperfusion following myocardial ischemia can prevent death by restoring nutrient flow, ischemia/reperfusion injury can cause significant heart damage. The mechanisms that drive ischemia/reperfusion injury are not well understood; currently, few methods can predict the state of the cardiac muscle cell and its metabolic conditions during ischemia. Here, we explored the energetic sustainability of cardiomyocytes, using a model for cellular metabolism to predict the levels of ATP following hypoxia. We modeled glycolytic metabolism with a system of coupled ordinary differential equations describing the individual metabolic reactions within the cardiomyocyte over time. Reduced oxygen levels and ATP consumption rates were simulated to characterize metabolite responses to ischemia. By tracking biochemical species within the cell, our model enables prediction of the cell’s condition up to the moment of reperfusion. The simulations revealed a distinct transition between energetically sustainable and unsustainable ATP concentrations for various energetic demands. Our model illustrates how even low oxygen concentrations allow the cell to perform essential functions. We found that the oxygen level required for a sustainable level of ATP increases roughly linearly with the ATP consumption rate. An extracellular O2 concentration of ~0.007 mM could supply basic energy needs in non-beating cardiomyocytes, suggesting that increased collateral circulation may provide an important source of oxygen to sustain the cardiomyocyte during extended ischemia. Our model provides a time-dependent framework for studying various intervention strategies to change the outcome of reperfusion.
2024-09-02 | BIOMD0000000961 | BioModels
Project description:Biofilms have been implicated in delayed wound healing, although the mechanisms by which biofilms impair wound healing are poorly understood. Many species of bacteria produce exotoxins and exoenzymes that may inhibit healing. In addition, oxygen consumption by biofilms, as well as responding leukocytes, may impede wound healing. In this study, we used oxygen microsensors to measure oxygen transects through in vitro-cultured biofilms, biofilms formed in vivo within scabs from a diabetic (db/db) mouse model, and ex vivo human chronic wound specimens. The results show that oxygen levels within mouse scabs had steep gradients that reached minima ranging from 17-72 mmHg on live mice and 6.4-1.1 mmHg on euthanized mice. The oxygen gradients in the mouse scabs were similar to those observed for clinical isolates cultured in vitro and for human ex vivo specimens. No oxygen gradients were observed for heat-killed mouse scabs, suggesting that active metabolism by the viable bacteria and host cells contributed to the reduced oxygen partial pressure of the scabs. To characterize the metabolic activities of the bacteria in the mouse scabs, we performed transcriptomics analyses of Pseudomonas aeruginosa biofilms associated with the db/db mice wounds using Affymetrix microarrays. The results demonstrated that the bacteria expressed genes for metabolic activities associated with cell growth. Interestingly, the transcriptome results indicated that the bacteria within the wounds also experienced oxygen-limitation stress. Among the bacterial genes that were expressed in vivo were genes associated with the Anr-mediated hypoxia-stress response. Other bacterial stress response genes highly expressed in vivo were genes associated with stationary-phase growth, osmotic stress, and RpoH-mediated heat shock stress. Overall, the results support the hypothesis that bacterial biofilms in chronic wounds promote chronicity by contributing to the maintenance of localized low oxygen tensions.
2015-09-30 | GSE66269 | GEO