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| Status |
Public on May 16, 2022 |
| Title |
ATF4 Protects the Heart from Failure by Antagonizing Oxidative Stress |
| Organisms |
Mus musculus; Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
There is 18 sample in this RNA-seq data. The samples 1-6 all treat with sham surgery which can be divided into two groups: 3 samples for ctrl group and 3 samples for cKO group. The samples 7-12 all treat with TAC surgery for 3 days, which can also be divided into two groups: 3 samples for ctrl group and 3 samples for cKO group. The samples 13-18 all treat with TAC surgery for 7 days, which can also be divided into two groups: 3 samples for ctrl group and 3 samples for cKO group.
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| Contributor(s) |
Wang X, Zhang G, Dasgupta S, Li C, Li Q, Tan L, Lorenzi PL, Rothermel BA, Scherer PE, Hill JA |
| Citation(s) |
35574856 |
| Submission date |
Nov 02, 2021 |
| Last update date |
May 16, 2022 |
| Contact name |
GUANGYU ZHANG |
| E-mail(s) |
zgy690511128@gmail.com
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| Phone |
7038142505
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| Organization name |
UTsouthwestern Medical Center
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| Department |
Cardiology
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| Lab |
Zhao Wang Lab
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| Street address |
5323 Harry Hines Blvd
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| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75390 |
| Country |
USA |
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| Platforms (2) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL14844 |
Illumina HiSeq 2000 (Rattus norvegicus) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA777255 |
| SRA |
SRP344236 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE187005_FPKM.txt.gz |
333.2 Kb |
(ftp)(http) |
TXT |
| GSE187005_adGFP_vs_adATF4.total_genes.xls.xlsx |
1.9 Mb |
(ftp)(http) |
XLSX |
| GSE187005_all_compare.xlsx |
26.3 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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