ATF3 in atherosclerosis: a controversial transcription factor

Wang, Bingyu; Yang, Xi; Sun, Xi; Liu, Jianhui; Fu, Yin; Liu, Bingyang; Qiu, Jun; Lian, Jing; Zhou, Jian

doi:10.1007/s00109-022-02263-7

Cited by 15 publications

(9 citation statements)

References 97 publications

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“…3 In addition, KLF4 has been reported to be an important regulator within macrophages. 11 Besides KLF2/4/6 , other top key drivers in GRN33 were also compelling: ATF3 (a negative regulator of inflammation-promoting cholesterol metabolism in macrophages 33 ), CEBPD (a promoter of lipid accumulation in M1-type macrophage in the atherosclerotic lesion 34 ), EGR1-3 (early growth response transcription factors regulating the expression of proteins such as IL1B and CXCL2 [C-X-C Motif Chemokine Ligand 2]), FOS / FOSB / FOSL1&2 and JUN / JUNB / JUND (FOS and JUN [Jun Proto-Oncogene] are involved in formation of foam cells 35,36 and the FOS and JUN families form the transcription factor complex AP-1 (Transcription Factor Subunit) a key regulator of cell proliferation, differentiation, and transformation), MYC / MXD1 (forming the MAX transcription factor involved in regulating cellular transformation), NFIL3 (activates ATFs [see ATF3 above]), and NR4A1-3 (the 3 family members of nuclear receptor subfamily 4 group, which is part of the steroid-thyroid hormone-retinoid receptor superfamily). Taken together, the overarching picture of these key drivers suggests that in the advanced stages of atherosclerosis, GRN33 promotes the formation of M1-type macrophages, resulting in symptomatic plaques likely through lipid accumulation and increased inflammation.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

Mocci,

Sukhavasi,

Örd

et al. 2024

Circulation Research

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BACKGROUND: While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood. METHODS: Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in nearly 19 000 single cells isolated during atherosclerosis progression in Ldlr −/− Apob 100/100 mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study. RESULTS: Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity (SYNTAX/Duke scores). The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers, FRZB and ALCAM , in cultured human vascular SMCs. CONCLUSIONS: By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced-stage, symptomatic atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

Mocci,

Sukhavasi,

Örd

et al. 2024

Circulation Research

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“…This indicated the pathological effect of ATF3 in diabetes [ 39 , 40 , 41 ]. There is a positive feedback loop between ATF3 and oxidative stress [ 42 , 43 ]. Moreover, ATF3 could promote erastin-induced ferroptosis by repressing SLC7A11 expression and suppressing system Xc [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury

Huo

Wang

Shi

et al. 2023

IJMS

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Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.

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“…IL-11 supports myofibroblast differentiation and activation, as well as ECM deposition, reinforcing the fibrotic infrastructure ( 55 ). Further to these factors, TGF-β signaling upregulates transcription factors such as c-JUN, JUN-B, and JUN-D ( 56 ). These factors dimerize with c-FOS and related proteins to form the AP-1 transcription complex, positioning it as a driver of fibrosis ( 57 ).…”

Section: Molecular Mechanisms Of Fibrosismentioning

confidence: 99%

Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis

Wang,

Chen,

Bao

et al. 2024

Front. Immunol.

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This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on the transition from acute radiation damage to a chronic fibrotic state. It reviewed the cellular and molecular responses of the skin to radiation, highlighting the role of myofibroblasts and the significant impact of Transforming Growth Factor-beta (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The review delves into the epigenetic regulation of fibrotic gene expression, the contribution of extracellular matrix proteins to the fibrotic microenvironment, and the regulation of the immune system in the context of fibrosis. Additionally, it discusses the potential of biomaterials and artificial intelligence in medical research to advance the understanding and treatment of radiation-induced skin fibrosis, suggesting future directions involving bioinformatics and personalized therapeutic strategies to enhance patient quality of life.

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ATF3 in atherosclerosis: a controversial transcription factor

Cited by 15 publications

References 97 publications

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury

Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis

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