Deletion of the Activated Protein-1 Transcription Factor JunD Induces Oxidative Stress and Accelerates Age-Related Endothelial Dysfunction

Paneni, Francesco; Osto, Elena; Costantino, Sarah; Mateescu, Bogdan; Briand, Sylvie; Coppolino, Giuseppe; Perna, Enrico; Mocharla, Pavani; Akhmedov, Alexander; Kubant, Ruslan; Rohrer, Lucia; Maliński, Tadeusz; Camici, Giovanni G.; Matter, Christian M.; Mechta‐Grigoriou, Fatima; Volpe, Massimo; Lüscher, Thomas F.; Cosentino, Francesco

doi:10.1161/circulationaha.112.000826

Cited by 96 publications

(90 citation statements)

References 46 publications

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“…JunD knockout mice display a vascular phenotype resembling accelerated endothelial aging with an impairment of endothelium-dependent vasorelaxation, disruption of mitochondrial function, and increased oxidative stress (43). Expression of JunD was significantly decreased in uremic aortas, supporting the concept of uremia being a state of premature aging.…”

Section: Uremicmentioning

confidence: 78%

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Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Rukov

Gravesen

Mace

et al. 2016

American Journal of Physiology-Renal Physiology

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Rukov JL, Gravesen E, Mace ML, Hofman-Bang J, Vinther J, Andersen CB, Lewin E, Olgaard K. Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing. Am J Physiol Renal Physiol 310: F477-F491, 2016. First published January 6, 2016 doi:10.1152/ajprenal.00472.2015.-The development of vascular calcification (VC) in chronic uremia (CU) is a tightly regulated process controlled by factors promoting and inhibiting mineralization. Next-generation high-throughput RNA sequencing (RNA-seq) is a powerful and sensitive tool for quantitative gene expression profiling and the detection of differentially expressed genes. In the present study, we, for the first time, used RNA-seq to examine rat aorta transcriptomes from CU rats compared with control rats. Severe VC was induced in CU rats, which lead to extensive changes in the transcriptional profile. Among the 10,153 genes with an expression level of Ͼ1 reads/kilobase transcript/million mapped reads, 2,663 genes were differentially expressed with 47% upregulated genes and 53% downregulated genes in uremic rats. Significantly deregulated genes were enriched for ontologies related to the extracellular matrix, response to wounding, organic substance, and ossification. The individually affected genes were of relevance to osteogenic transformation, tissue calcification, and Wnt modulation. Downregulation of the Klotho gene in uremia is believed to be involved in the development of VC, but it is debated whether the effect is caused by circulating Klotho only or if Klotho is produced locally in the vasculature. We found that Klotho was neither expressed in the normal aorta nor calcified aorta by RNA-seq. In conclusion, we demonstrated extensive changes in the transcriptional profile of the uremic calcified aorta, which were consistent with a shift in phenotype from vascular tissue toward an osteochondrocytic transcriptome profile. Moreover, neither the normal vasculature nor calcified vasculature in CU expresses Klotho.

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Section: Uremicmentioning

confidence: 78%

“…Expression of JunD was significantly decreased in uremic aortas, supporting the concept of uremia being a state of premature aging. JunD protooncogene expression has not been previously demonstrated in the uremic calcified vasculature, but recently an age-dependent downregulation of JunD has been shown in the endothelium (43).…”

Section: Uremicmentioning

confidence: 91%

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Rukov

Gravesen

Mace

et al. 2016

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

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“…Many of these endogenous antioxidant pathways are controlled by the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which binds to the antioxidant response elements (ARE) in the promoter regions of genes to induce upregulation of antioxidant enzymes such as glutathione, manganese (mitochondrial) superoxide dismutase (SOD2), and heme oxygenase (86, 109). Recent work also indicates an important role for the activated protein-1 transcription factor JunD in regulating vascular superoxide, antioxidant pathways, NO bioavailability, and endothelial function with aging in mice (137).…”

Section: Critical Upstream Homeostatic and Stress Resistance Pathwaysmentioning

confidence: 99%

You're Only as Old as Your Arteries: Translational Strategies for Preserving Vascular Endothelial Function with Aging

et al. 2014

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Endothelial dysfunction develops with age and increases the risk of age-associated vascular disorders. Nitric oxide insufficiency, oxidative stress, and chronic low-grade inflammation, induced by upregulation of adverse cellular signaling processes and imbalances in stress resistance pathways, mediate endothelial dysfunction with aging. Healthy lifestyle behaviors preserve endothelial function with aging by inhibiting these mechanisms, and novel nutraceutical compounds that favorably modulate these pathways hold promise as a complementary approach for preserving endothelial health.

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“…DAPK1 has been shown to be indispensable in cell death mediated by IFN-␥, transforming growth factor ␤ (TGF-␤), TNF-␣, DNA damage, and oxidative stress (reviewed in reference 35). JunD has a cytoprotective role in the response to oxidative stress in several cell types (36)(37)(38)(39)(40)(41). Preliminary analyses indicated that v-Src-transformed CEFs expressing TAM67 or the junD shRNA have elevated levels of reactive oxygen species (our unpublished results).…”

Section: Discussionmentioning

confidence: 79%

JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells

Maslikowski

Wang

et al. 2017

J Virol

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The increase in AP-1 activity is a hallmark of cell transformation by tyrosine kinases. Previously, we reported that blocking AP-1 using the c-Jun dominant negative mutant TAM67 induced senescence, adipogenesis, or apoptosis in v-Srctransformed chicken embryo fibroblasts (CEFs) whereas inhibition of JunD by short hairpin RNA (shRNA) specifically induced apoptosis. To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEFs expressing either TAM67 or the JunD shRNA. Our study revealed a cluster of 18 probe sets upregulated exclusively in response to AP-1/JunD impairment and v-Src transformation. Four of these probe sets correspond to genes involved in the interferon pathway. One gene in particular, death-associated protein kinase 1 (DAPK1), is a C/EBP␤-regulated mediator of apoptosis in gamma interferon (IFN-␥)-induced cell death. Here, we show that inhibition of DAPK1 abrogates cell death in v-Src-transformed cells expressing the JunD shRNA. Chromatin immunoprecipitation data indicated that C/EBP␤ was recruited to the DAPK1 promoter while the expression of a dominant negative mutant of C/EBP␤ abrogated the induction of DAPK1 in response to the inhibition of AP-1. In contrast, as determined by chromatin immunoprecipitation (ChIP) assays, JunD was not detected on the DAPK1 promoter under any conditions, suggesting that JunD promotes survival by indirectly antagonizing the expression of DAPK1 in v-Src transformed cells.IMPORTANCE Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-B and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1.KEYWORDS AP-1, C/EBP␤, DAPK1, JunD, transformation, v-Src T he Src nonreceptor tyrosine kinase has served as the prototypical kinase model for signaling in vertebrates. Understanding the fundamental basis for Src signaling has provided insight into both the normal function of kinase signaling in the cell as well as contributing to the understanding of human disease. In particular, high Src activity has been linked to poor prognosis and metastasis in breast and colon cancers (1, 2). Given Src's role in human disease, v...

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Deletion of the Activated Protein-1 Transcription Factor JunD Induces Oxidative Stress and Accelerates Age-Related Endothelial Dysfunction

Cited by 96 publications

References 46 publications

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

You're Only as Old as Your Arteries: Translational Strategies for Preserving Vascular Endothelial Function with Aging

JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells

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