Fibrillin-1-regulated miR-122 has a critical role in thoracic aortic aneurysm formation

Zhang, Rong-Mo; Tiedemann, Kerstin; Muthu, Muthu L.; Dinesh, Neha E. H.; Komarova, Svetlana V.; Ramkhelawon, Bhama; Reinhardt, Dieter P.

doi:10.1007/s00018-022-04337-8

Cited by 17 publications

(24 citation statements)

References 73 publications

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“…Our finding of decreased exosomal miR-122 expression in AAA patients may be closely linked to the role miR-122 plays in regulating extracellular matrix (ECM) processing by matrix metalloproteinases (MMPs) [ 32 ]. Network analyses demonstrated that several MMPs are potential targets of miR-122-5p, with MMP2 and MMP7 being ranked the highest.…”

Section: Discussionmentioning

confidence: 99%

“…AAA formation is initiated by an influx of immune cells that secrete inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1) and activate metalloproteinases, resulting in smooth muscle apoptosis, extracellular matrix degradation, and elastin fragmentation [ 44 , 45 ]. In fact, recently miR-122-5p has recently been identified to play a critical role in the formation of thoracic aortic aneurysms in a mouse model [ 32 ]. In this model, miR-122-5p was shown to regulate inflammatory cytokines and matrix remodeling within the aortic wall.…”

Section: Discussionmentioning

confidence: 99%

“…formation of thoracic aortic aneurysms in a mouse model [32]. In this model, miR-122-5p was shown to regulate inflammatory cytokines and matrix remodeling within the aortic wall.…”

Section: Plos Onementioning

confidence: 91%

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Patients with abdominal aortic aneurysms have reduced levels of microRNA 122-5p in circulating exosomes

et al. 2023

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Objective There are currently no specific biomarkers to identify patients with abdominal aortic aneurysms (AAAs). Circulating exosomes contain microRNAs (miRNA) that are potential biomarkers for the presence of disease. This study aimed to characterize the exosomal miRNA expression profile of patients with AAAs in order to identify novel biomarkers of disease. Methods Patients undergoing duplex ultrasound (US) or computed tomography (CT) for screening or surveillance of an AAA were screened to participate in the study. Cases with AAA were defined as having a max aortic diameter >3 cm. Circulating plasma exosomes were isolated using Cushioned-Density Gradient Ultracentrifugation and total RNA was extracted. Next Generation Sequencing was performed on the Illumina HiSeq4000 SE50. Differential miRNA expression analysis was performed using DESeq2 software with a Benjamini-Hochberg correction. MicroRNA expression profiles were validated by Quantitative Real-Time PCR. Results A total of 109 patients were screened to participate in the study. Eleven patients with AAA and 15 non-aneurysmal controls met study criteria and were enrolled. Ultrasound measured aortic diameter was significantly larger in the AAA group (mean maximum diameter 4.3 vs 2.0 cm, P = 6.45x10-6). More AAA patients had coronary artery disease (5/11 vs 1/15, P = 0.05) as compared to controls, but the groups did not differ significantly in the rates of peripheral arterial disease and chronic obstructive pulmonary disease. A total of 40 miRNAs were differentially expressed (P<0.05). Of these, 18 miRNAs were downregulated and 22 were upregulated in the AAA group compared to controls. After false discovery rate (FDR) adjustment, only miR-122-5p was expressed at significantly different levels in the AAA group compared to controls (fold change = 5.03 controls vs AAA; raw P = 1.8x10-5; FDR P = 0.02). Conclusion Plasma exosomes from AAA patients have significantly reduced levels of miRNA-122-5p compared to controls. This is a novel exosome-associated miRNA that warrants further investigation to determine its use as a diagnostic biomarker and potential implications in AAA pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Patients with abdominal aortic aneurysms have reduced levels of microRNA 122-5p in circulating exosomes

et al. 2023

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“…Accumulating evidence suggests the involvement of an inflammatory response in the pathogenesis of MFS. 18,37,[49][50][51][52][53] However, precise understanding of causes and consequences of inflammation and particularly the role of the innate immune system in MFS is lacking, and previous findings have not yet been translated to clinically available treatment strategies specifically targeting MFS-related immune responses. MPO is one of the most abundant proteins in neutrophils and critically involved in many cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of myeloperoxidase attenuates thoracic aortic aneurysm formation in Marfan disease

Mehrkens

Nettersheim

Ballmann

et al. 2022

Preprint

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Marfan syndrome (MFS) is a prevalent inherited connective tissue disorder associated with premature mortality due to thoracic aortic aneurysms and subsequent fatal aortic events. Current treatment options improve outcomes only partially and better preventive pharmacotherapies are needed. By utilizing patient samples and animal disease models, we herein demonstrate that leukocyte-derived myeloperoxidase (MPO) critically contributes to disease progression. MFS patients and mice displayed increased circulating MPO levels as well as marked aortic MPO deposition compared to controls. Mechanistically, MPO induced inflammatory endothelial activation and endothelial-to-mesenchymal transition which triggered aortic leukocyte recruitment. Furthermore, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitrosylation of extracellular matrix proteins. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and a promising target to influence disease progression.

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“…One study reported that the reduced miR-122 in TAA was related with brillin-1 de ciency, in ammatory response and degradation of elastic laminae 17 . Another study reported miR-574-5p might increase in the plasma of mice with the Marfan Syndrome model and decrease in the aortic tissue of TAA patients 18 .…”

Section: Introductionmentioning

confidence: 99%

Expression pattern of Autophagy-related Genes and Immune Infiltration Landscape in Thoracic Aortic Aneurysm

Zhu

et al. 2022

Preprint

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Thoracic aortic aneurysm (TAA), a life-threatening cardiovascular disease, is considered a common cause of death in older individuals. Studies on the molecular mechanism of TAA are very limited. The aim of this study is to explore the expression pattern of autophagy-related genes (ARGs) in TAA, and the related immune infiltration landscape, using bioinformatics analysis. Differentially expressed genes (DEGs) in GSE26155 and differentially expressed miRNAs in GSE110527 were screened by R software. GO annotation and KEGG pathway enrichment analysis were performed on these DEGs. STRING database was employed for the PPI network establishment which was visualized by Cytoscape software. The differentially expressed ARGs were obtained by merging these DEGs with ARGs in autophagy databases HAMDb and HADb. The expression patterns of these differentially expressed ARGs are shown by violin diagram, correlation heatmap, PPI network and enrichment analysis. ROC analysis was used to evaluated the diagnostic value of these differentially expressed ARGs in TAA. Genes with area under the curve (AUC) > 0.7 were considered as TAA biomarkers. TargetScan, miRDB and miRWalk databases were used to predict miRNAs that target these ARGs. Intersection of predicted miRNAs and differentially expressed miRNAs to screen miRNAs that have a clear regulatory relationship with genes. Then a miRNA-mRNA regulatory network was constructed. Following this, the immune infiltration landscape of TAA and the correlation between these ARGs and immunity were further analyzed. In this study, 15 differentially expressed ARGs were screened and the expression patterns of these ARGs were investigated. A miRNA-mRNA regulatory network was constructed. 13 genes with AUC>0.7 in these differentially expressed ARGs were recognized as TAA biomarkers. Finally, the immune infiltration landscape of TAA was shown.

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Fibrillin-1-regulated miR-122 has a critical role in thoracic aortic aneurysm formation

Cited by 17 publications

References 73 publications

Patients with abdominal aortic aneurysms have reduced levels of microRNA 122-5p in circulating exosomes

Patients with abdominal aortic aneurysms have reduced levels of microRNA 122-5p in circulating exosomes

Inhibition of myeloperoxidase attenuates thoracic aortic aneurysm formation in Marfan disease

Expression pattern of Autophagy-related Genes and Immune Infiltration Landscape in Thoracic Aortic Aneurysm

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