Vascular smooth muscle cell senescence instigates thoracic aortic aneurysm
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143921 | GEO | 2023/12/01
REPOSITORIES: GEO
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Project description:Thoracic Aortic Aneurysm (TAA) is characterized by the dilation and degradation of the aorta and is fatal if not diagnosed and treated appropriately. There are no specific clinical symptoms, so better knowledge of the physiopathology of TAAs and their underlying genetic mechanisms is needed to improve diagnosis and therapy. MiRNAs regulate gene expression post-transcriptionally and are known to be involved in cerebrovascular disease. The current study aimed to identify differentially expressed miRNAs in patients with TAAs and determine whether their predicted target genes could be associated with this condition. Nanostring assays identified miRNAs in plasma and tissue samples from four TAA patients. RT-PCR validated the expression levels of these miRNAs in a further 22 plasma samples. Three, hsa-miR140-5p, hsa-miR-191-5p and hsa-miR-214-3p showed significant expression level differences between plasma samples collected pre- and post-surgically from each patient. Analyses of the predicted target gene controlled by these miRNAs revealed nine genes whose expression was investigated in the same 22 plasma samples. The gene expression levels were inversely correlated with the expression of their respective miRNAs. From these, CCND2, CRKL, HEY1, MTMR4, NFIA and PPP1CB, showed fold-change differences >1.5 between the two plasma samples. An in-depth literature search and Cytoscape software three genes; MTMR4, NFIA and PPP1CB, showed a possible association with the TGF-β signalling pathway. It is suggested that the three miRNAs detected together with their target genes could play a role in the TGF-β signalling pathway and thus be involved in TAA pathogenesis.
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Project description:Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain–containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell–specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.
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Project description:We report dynamic temporal and spatial smooth muscle cell phenotype modulation using aortic single cell RNA sequencing in a murine model of Marfan syndrome (Fbn1C1041G/+) and littermate controls. Aortic root/ascending aortic tissue samples from both genotypes were studied at 4 and 24 weeks of age. The non-aneurysmal descending thoracic aorta was also studied at 24 weeks. Finally human aortic tissue from a Marfan syndrome patient undergoing aneurysm repair surgery was studied.
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Project description:Genome wide DNA methylation profiling of normal and ascending aorta tissue samples from normal and aortic dissection patients. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 485,512 CpGs in ascending aorta tissue samples. Samples included 4 normal donors and 4 patients with aortic dissection.
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Project description:Bicuspid aortic valve is well known as a risk factor of dilation of ascending aorta. But the mechanisms of dialation are unknown. Morever, patients with bicuspid aortic valve tend to be aortic valve disease at younger age. After aortic valve surgery, if ascending aorta is dilated, the patient must be performed re-operation. For that reason, surgery for aortic root or ascending aorta is recommended to patient with bicuspid aortic valve with dilated ascending aorta. We thought that abnormality of cell cycle of the structure protein participated in ascending aorta dilation of patient with bicuspid aortic valve. We resected the wall of the ascending aota from patient undergoing aortic valve replacement for aortic valve stenosis during operation, and performed immunohistochemical staining for akt. Anti Akt antibodys were stained much on aortic media with bicuspoed aortic valve. Akt is a protein that is involved in mTOR / PI3K, and modulate the cell differenciation and proliferation. Further, the same samples were analyzed using a microarray method. On bicuspid aortic valve patients, the expression of TSC2 is reduced, and GβL is increased. TSC2 inhibit this pathway, and MLST8 activate this pathway. In the ascending aorta of BAV patients, PI3K / mTOR system is considered to be activated. When this pathway is activated, cell proliferation and cytodifferentiation are promoted abnormally,
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