Nucleolar stress induces a senescence-like phenotype in smooth muscle cells and promotes development of vascular degeneration

Zhang, Wenjing; Cheng, Wen Po; Parlato, Rosanna; Guo, Xinfeng; Cui, Xiaopei; Dai, Chaochao; Xu, Lei; Zhu, Jiankang; Zhu, Min; Luo, Kun; Zhang, Wencheng; Dong, Bo; Wang, Jianli; Jiang, Fan

doi:10.18632/aging.104094

Cited by 20 publications

(17 citation statements)

References 56 publications

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“…The most enriched GO terms were RNA catabolic process, regulation of translation, ribosomal subunit, cell-substrate junction, focal adhesion, ubiquitin-like protein ligase binding, transcription coregulator activity, et al The pathways enriched by KEGG were linked to ribosome, coronavirus diseases-COVID-19, RNA transport, cell cycle, et al Some of these functions and pathways have been reported to accelerate the onset and development of AAA. 24 For example, Zhang et al found that perturbed ribosomal DNA transcription and induction of nucleolar stress in SMCs that elicited cell cycle arrest could contribute to the pathogenesis of AAA, 25 while Harada et al showed that focal adhesion kinase facilitated sustained aortic inflammation and AAA progression by modulating macrophage behavior. 26 A recent study has reported that COVID-19 may theoretically influence AAA disease through multiple SARS-CoV-2-induced mechanisms, but whether and to what extent the COVID-19 pandemic will influence the prevalence, progression, and lethality of AAA is unclear.…”

Section: Discussionmentioning

confidence: 99%

Expression Pattern and Clinical Value of Key m6A RNA Modification Regulators in Abdominal Aortic Aneurysm

Wang

Jing

et al. 2021

JIR

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Background Aberrant expression of N6-methyladenosine (m6A) RNA modification regulators plays a critical role in a variety of human diseases. However, their implication in abdominal aortic aneurysm (AAA) remains largely unknown. Herein, we sought to explore the general expression pattern and potential functions of m6A regulators in AAA. Methods We analyzed gene expression data of m6A regulators in human AAA and normal tissues from public GEO database. The R package and other tools such as m6A2Target database, Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses, gene set variation analysis (GSVA), Search Tool for the Retrieval of Interacting Genes (STRING), starBase, miRDB and Cytoscape software were applied for bioinformatics analysis to investigate the downstream molecular mechanisms and upstream regulatory mechanisms for distinctly expressed regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to validate the expression of key m6A regulators in our collected human AAA specimens. Results We found that METTL14 and HNRNPC were the downregulated m6A regulators, and RBM15B was the upregulated methylation transferase in human AAA. The modified genes were primarily enriched in RNA catabolic process, regulation of translation, focal adhesion, transcription coregulator activity, ribosome, RNA transport, cell cycle, et al. METTL14, HNRNPC and RBM15B levels were correlated with the immune infiltration degree of Tcm, macrophages, mast cells, Tgd and NK CD56bright cells. A total of 154 and 76 target genes of three regulators were separately involved in body metabolism and autophagy in AAA disease, and their interactive relationships and hub genes were identified. The lncRNA-miRNA-mRNA interaction regulatory networks were also constructed for METTL14, HNRNPC and RBM15B. Based on our clinical tissue and serum samples, METTL14 exhibited lower expression levels in AAA and its rupture type, and low METTL14 expression was associated with high levels of WBC and CRP (all P < 0.05). Conclusion Our study presents an overview of the expression pattern and functional significance of m6A regulators in human AAA. Our findings will provide a valuable resource that may guide both mechanistic and therapeutic analyses about the role of key m6A regulators in AAA.

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Section: Discussionmentioning

confidence: 99%

Expression Pattern and Clinical Value of Key m6A RNA Modification Regulators in Abdominal Aortic Aneurysm

Wang

Jing

et al. 2021

JIR

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“…The pathophysiology of AAA is highly complex, with elastic tissue degeneration, inflammation, VSMCs dysfunction and accelerated oxidative stress [ 107 ]. More importantly, recent studies have linked cellular senescence to AAA pathogenesis [ 75 - 77 , 108 ]. SIRT1 inhibition accelerated vascular cell senescence and facilitated the transcriptional activation of nuclear factor-κB (NF-κB) signaling, which promoted the formation and rupture of AAAs [ 75 ].…”

Section: Consequence Of Cellular Senescence In Cardiovascular Diseasesmentioning

confidence: 99%

Cellular Senescence in Cardiovascular Diseases: A Systematic Review

Hu¹,

Zhang²,

Teng³

et al. 2022

Aging and disease

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Aging is a prominent risk factor for cardiovascular diseases, which is the leading cause of death around the world. Recently, cellular senescence has received potential attention as a promising target in preventing cardiovascular diseases, including acute myocardial infarction, atherosclerosis, cardiac aging, pressure overload-induced hypertrophy, heart regeneration, hypertension, and abdominal aortic aneurysm. Here, we discuss the mechanisms underlying cellular senescence and describe the involvement of senescent cardiovascular cells (including cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts/myofibroblasts and T cells) in age-related cardiovascular diseases. Then, we highlight the targets (SIRT1 and mTOR) that regulating cellular senescence in cardiovascular disorders. Furthermore, we review the evidence that senescent cells can exert both beneficial and detrimental implications in cardiovascular diseases on a context-dependent manner. Finally, we summarize the emerging pro-senescent or anti-senescent interventions and discuss their therapeutic potential in preventing cardiovascular diseases.

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“…Errors in rDNA transcription, rRNA processing, and ribosome assembly are the cause of several disorders collectively named ribosomopathies. These include degenerative dis-eases such as abdominal aortic aneurysm [28,29] and Parkinson's disease [30], along with developmental disorders such as Treacher Collins syndrome [31,32], Diamond-Blackfan anemia [33][34][35], Bowen-Conradi syndrome [36], and autosomal recessive primary microcephaly [37].…”

Section: Nucleolar Structure and Organization Allow For Flexibility I...mentioning

confidence: 99%

Regulation of Nucleolar Activity by MYC

Brown

Lafita-Navarro

Conacci‐Sorrell

2022

Cells

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The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo continuous proliferation; therefore, nucleolar activity is elevated due to their high demand for protein synthesis. The transcription factor and universal oncogene MYC promotes nucleolar activity by enhancing the transcription of ribosomal DNA (rDNA) and ribosomal proteins. This review summarizes the importance of nucleolar activity in mammalian cells, MYC’s role in nucleolar regulation in cancer, and discusses how a better understanding (and the potential inhibition) of aberrant nucleolar activity in cancer cells could lead to novel therapeutics.

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Nucleolar stress induces a senescence-like phenotype in smooth muscle cells and promotes development of vascular degeneration

Cited by 20 publications

References 56 publications

Expression Pattern and Clinical Value of Key m6A RNA Modification Regulators in Abdominal Aortic Aneurysm

Expression Pattern and Clinical Value of Key m6A RNA Modification Regulators in Abdominal Aortic Aneurysm

Cellular Senescence in Cardiovascular Diseases: A Systematic Review

Regulation of Nucleolar Activity by MYC

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