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Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

ABSTRACT: Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

PROVIDER: PRJNA1104590 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28809942.fastq.gz	Fastqsanger.gz
	SRR28809943.fastq.gz	Fastqsanger.gz
	SRR28809944.fastq.gz	Fastqsanger.gz
	SRR28809945.fastq.gz	Fastqsanger.gz
	SRR28809946.fastq.gz	Fastqsanger.gz

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Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

Project description:Aortic aneurysms are dilations of the aorta that can rupture when left untreated. We used aneurysmal Fibulin-4R/R to further unravel the underlying mechanisms of aneurysm formation. RNA sequencing of 3-month-old Fibulin-4R/R aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of Fibulin-4R/R VSMCs by revealing increased SA-β-gal, p21 and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of Fibulin-4R/R|p21-Luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that Fibulin-4R/R aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK/STAT and TGF-β pathway inhibition as well as senolytic treatment on Fibulin-4R/R VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.

2024-04-30 | GSE265869 | GEO

Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice.

Project description:Aortic aneurysms are dilatations of the aorta that can rupture when left untreated. We used the aneurysmal Fibulin-4R/R mouse model to further unravel the underlying mechanisms of aneurysm formation. RNA sequencing of 3-month-old Fibulin-4R/R aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating the involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of Fibulin-4R/R VSMCs by revealing increased SA-β-gal, p21, and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of Fibulin-4R/R|p21-luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that Fibulin-4R/R aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK/STAT and TGF-β pathway inhibition, as well as senolytic treatment on Fibulin-4R/R VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.

| S-EPMC11189919 | biostudies-literature

Transcription profiling of aorta from mice underexpressing Fibulin-4 to investigate its role in elastic fibre assembly and cardio-vasuclar disease

Project description:Extracellular elastic fibres apply structure and mechanical elasticity to organs such as large arteries, lungs and skin 1. Elastic fibres are assembled through polymerization of tropoelastin monomers and loss of elastin is associated with aneurysmal degeneration of the aorta 2. The Fibulins are a six-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures such as elastic fibres and basement membranes 3. Fibulin-4 is found in the medial layers of arteries and moderately expressed in heart valves 4. To examine a potential role of Fibulin-4 in elastic fibre assembly and cardio-vascular disease we generated a mouse model underexpressing Fibulin-4. To get insight into the underlying molecular pathways involved in aneurysm formation, we determined the aorta transcriptome of Fibulin-4R/R animals and identified biological processes that were significantly overrepresented including apoptosis and cell death as well as several novel gene targets implicated in the response to aortic failure. We conclude that decreased Fibulin-4 expression causes aberrant composition of the elastin layers in the aorta and valvular leaflets, resulting in aortic aneurysms and heart abnormalities.

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Project description:In this study, we identified various cell clusters in human normal/sporadic TAA ascending aorta samples by single-cell RNA sequencing (scRNA-seq), and discovered the senescent vascular smooth muscle cells (VSMCs) significantly increased in TAA samples. Then we explored the molecular basis of TAA progression, and recognized the key regulators and pathways involved in the TAA progression regulation.

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Effect of fibulin-3 knockdown on malignant mesothelioma cells

Project description:Whole transcriptome comparison of mesothelioma cells transfected with control vs Fibulin-3 (EFEMP1) siRNAs. Mesothelioma cells H-226 (ATCC) and H-2595 (Harvey Pass, New York University) were transfected with two fibulin-3 or control siRNAs and collected 48h after transfection. Gene expression was quantified by RNAseq using standard procedures. The results suggest that downregulation of fibulin-3 negatively affects a PI3K/AKT-dependent gene signature involved in cell growth, adhesion, and association with the extracellular matrix.

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Altered microRNA expression: Control vs. Intracranial Aneurysmal Tissues

Project description:High throughput miRNA microarray screening approach, we compared the miRNA expression pattern in ruptured aneurysm tissues obtained during surgery from patients with aneurysmal subarachnoid hemorrhage (aSAH) with control tissues. Aim was to determine miRNA signature in aneurysmal tissues.

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MERSCOPE profiling of non-aneurysmal and aneurysmal human ascending aorta

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