ATF4 Protects the Heart from Failure by Antagonizing Oxidative Stress
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ABSTRACT:
PROVIDER: PRJNA777255 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16700921_1.fastq.gz | Fastqsanger.gz | |||
| SRR16700921_2.fastq.gz | Fastqsanger.gz | |||
| SRR16700922.fastq.gz | Fastqsanger.gz | |||
| SRR16700923_1.fastq.gz | Fastqsanger.gz | |||
| SRR16700923_2.fastq.gz | Fastqsanger.gz |
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Project description:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Here, we show that production of cardiomyocyte NADPH (nicotinamide adenine dinucleotide phosphate), a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with cardiac cell death, fibrosis, and cardiomyopathy. We report that the pentose phosphate pathway (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two major NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced in the heart by pressure overload. We identify ATF4 (activating transcriptional factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistent with this, joint pathway analysis (JPA) of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in cardiomyocytes in culture leads to a significant increase in NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression in vitro strongly augments metabolic flux within these two pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of pressure overload and accelerates the development of heart failure, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Taken together, our findings reveal that ATF4 plays a critical role in cardiac homeostasis under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
2022-05-16 | GSE187005 | GEO
Project description:Oxidative stress is pathogenic in neurological diseases including stroke. The identity of oxidative stress-inducible transcription factors and their role(s) in propagating the death cascade are poorly understood. Microarray analysis of neurons undergoing oxidative stress showed significant induction of prodeath genes. These genes have been shown to be regulated by the bZip transcription factor, ATF4. ATF4 protein localized to the promoter of a putative death gene in neurons in vitro and in vivo. Germline deletion of ATF4 in neurons resulted in a reduction in oxidative stress-induced gene expression and resistance to oxidative death. ATF4 knockout mice experienced significantly smaller infarcts and improved behavioral recovery as compared to wild-type mice subjected to the same reductions in blood flow in a rodent model of stroke. ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Restoration of ATF4 protein in knockout neurons was sufficient to restore sensitivity to oxidative death and to reaccelerate loss of glutathione. Together, these findings establish ATF4 as a redox-regulated, pro-death transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo. Keywords: ATF4, oxidative stress, gene expression, neuroprotection, stroke WT and ATF4 KO embryonic neurons were studied. Untreated neurons (no=8 per genotype) and neurons challenged with oxidative stress with the glutamate homolog homocysteate (HCA, no=4 per genotype) were studied, for a total of 24 samples.
2010-06-25 | E-GEOD-10470 | biostudies-arrayexpress
Project description:Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks and protects dopaminergic neurons against apoptosis. RNA-seq data for differentially expressed genes in the SNpc of En1+/- mice, En2 infused mice and 6-OHDA/En2 injection experiments.
2015-09-24 | E-GEOD-72321 | biostudies-arrayexpress
Project description:Oxidative stress is pathogenic in neurological diseases including stroke. The identity of oxidative stress-inducible transcription factors and their role(s) in propagating the death cascade are poorly understood. Microarray analysis of neurons undergoing oxidative stress showed significant induction of prodeath genes. These genes have been shown to be regulated by the bZip transcription factor, ATF4. ATF4 protein localized to the promoter of a putative death gene in neurons in vitro and in vivo. Germline deletion of ATF4 in neurons resulted in a reduction in oxidative stress-induced gene expression and resistance to oxidative death. ATF4 knockout mice experienced significantly smaller infarcts and improved behavioral recovery as compared to wild-type mice subjected to the same reductions in blood flow in a rodent model of stroke. ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Restoration of ATF4 protein in knockout neurons was sufficient to restore sensitivity to oxidative death and to reaccelerate loss of glutathione. Together, these findings establish ATF4 as a redox-regulated, pro-death transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo. Keywords: ATF4, oxidative stress, gene expression, neuroprotection, stroke
2008-03-01 | GSE10470 | GEO
Project description:Disability or death secondary to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron and generation of oxidative stress. Iron chelators bind free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms remain unclear. Here we show that the hypoxia-inducible factor prolylhydroxylase (HIF PHD) family of iron-dependent oxygen sensors is an effector of iron chelation in abrogating ICH-induced death. Molecular reduction of the three HIF PHD isoforms in mouse striatum improves functional recovery following ICH. A low molecular weight, hydroxyquinoline inhibitor of the HIF PHDs, which we call adaptaquin, reduces neuronal death and behavioral deficits following ICH in distinct rodent models. Unexpectedly, adaptaquin protects from oxidative death by suppressing ATF4- dependent prodeath gene expression rather than by activating a HIF-dependent prosurvival pathway. Adaptaquin treated neurons
2016-03-01 | E-GEOD-75048 | biostudies-arrayexpress
Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPβ and CHOP were largely dispensable for induction of stress genes. Cebpgâ/â MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ/â mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ/â mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPγ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. Evaluation of genomic binding of 2 bZIP transcription factors under amino acid deprivation conditions in mouse embryonic fibroblasts
2015-11-19 | E-GEOD-75165 | biostudies-arrayexpress
Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPβ and CHOP were largely dispensable for induction of stress genes. Cebpgâ??/â?? MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ??/â?? mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ??/â?? mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPγ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. WT, Atf4-/-, and Cebpg-/- MEFs (passage 3) were cultured under normal and AAD conditions. RNA from each treatment condition was collected in triplicate for hybrization on Affymetrix Mouse Genome 430 2.0 microarrays.
2015-11-19 | E-GEOD-75150 | biostudies-arrayexpress
Project description:Triclosan (TCS) is an antimicrobial toxicant found in a myriad of consumer products and has been detected in human tissues, including breastmilk. We have evaluated the impact of lactational TCS on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) neonatal mice. In hUGT1 mice, expression of the hepatic UGT1A1 gene is developmentally delayed resulting in elevated total serum bilirubin (TSB) levels. We found that newborn hUGT1 mice breastfed or orally treated with TCS presented lower TSB levels along with induction of hepatic UGT1A1. Lactational and oral treatment by gavage with TCS leads to the activation of hepatic nuclear receptors CAR, PPARα, and stress sensor, ATF4. When CAR-deficient hUGT1 mice (hUGT1/Car-/-) were treated with TCS, TSB levels were reduced with a robust induction of hepatic UGT1A1, leaving us to conclude that CAR is not tied to UGT1A1 induction. Alternatively, when PPAR-deficient hUGT1 mice (hUGT1/Ppar-/-) were treated with TCS, hepatic UGT1A1 was not induced. Additionally, we had previously demonstrated that TCS is a potent inducer of ATF4, a transcriptional factor linked to the integrated stress response. When ATF4 was deleted in liver of hUGT1 mice (hUGT1/Atf4∆Hep), and these mice treated with TCS, we observed superinduction of hepatic UGT1A1. Oxidative stress genes in livers of hUGT1/Atf4∆Hep treated with TCS were increased, suggesting that ATF4 protects liver from excessive oxidative stress. The increase oxidative stress may be associated with superinduction of UGT1A1. The expression of ATF4 in neonatal hUGT1 hepatic tissue may play a role in the developmental repression of UGT1A1.
2024-04-24 | GSE264293 | GEO
Project description:Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks and protects dopaminergic neurons against apoptosis.
2015-09-24 | GSE72321 | GEO
Project description:For additional details see Ebert et al, Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Quadriceps femoris muscles were harvested from 22-month-old muscle-specfic ATF4 knockout (ATF4 mKO) mice and littermate controls. mRNA levels in ATF4 mKO muscles were normalized to levels in littermate control muscles.
2015-09-03 | E-GEOD-72658 | biostudies-arrayexpress