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Carotid artery ligation induced intimal thickening and proliferation is unaffected by ageing.

ABSTRACT: Following interventions to treat atherosclerosis, such as coronary artery bypass graft surgery, restenosis occurs in approximately 40% of patients. Identification of proteins regulating intimal thickening could represent targets to prevent restenosis. Our group previously demonstrated that in a murine model of vascular occlusion, Wnt4 protein expression and ?-catenin signalling was upregulated which promoted vascular smooth muscle cell (VSMC) proliferation and intimal thickening. In this study, the effect of age on VSMC proliferation, intimal hyperplasia and Wnt4 expression was investigated. In vitro proliferation of VSMCs isolated from young (2 month) or old (18-20 month) C57BL6/J mice was assessed by immunocytochemistry for EdU incorporation. As previously reported, 400 ng/mL recombinant Wnt4 protein increased proliferation of VSMCs from young mice. However, this response was absent in VSMCs from old mice. As our group previously reported reduced intimal hyperplasia in Wnt4^+/- mice compared to wildtype controls, we hypothesised that impaired Wnt4 signalling with age may result in reduced neointimal formation. To investigate this, carotid artery ligation was performed in young and old mice and neointimal area was assessed 21 days later. Surprisingly, neointimal area and percentage lumen occlusion were not significantly affected by age. Furthermore, neointimal cell density and proliferation were also unchanged. These data suggest that although Wnt4-mediated proliferation was impaired with age in primary VSMCs, carotid artery ligation induced neointimal formation and proliferation were unchanged in old mice. These results imply that Wnt4-mediated proliferation is unaffected by age in vivo, suggesting that therapeutic Wnt4 inhibition could inhibit restenosis in patients of all ages.

SUBMITTER: Brown BA

PROVIDER: S-EPMC6039339 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Carotid artery ligation induced intimal thickening and proliferation is unaffected by ageing.

Brown B A BA Williams H H Bond A R AR Angelini G D GD Johnson J L JL George S J SJ

Journal of cell communication and signaling 20171129 3

Following interventions to treat atherosclerosis, such as coronary artery bypass graft surgery, restenosis occurs in approximately 40% of patients. Identification of proteins regulating intimal thickening could represent targets to prevent restenosis. Our group previously demonstrated that in a murine model of vascular occlusion, Wnt4 protein expression and β-catenin signalling was upregulated which promoted vascular smooth muscle cell (VSMC) proliferation and intimal thickening. In this study, ...[more]

PMID: 29185213

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Project description:Intimal hyperplasia (IH) is a prominent pathological event that occurs during in-stent restenosis and atherosclerosis. Ferroptosis, characterized by iron-dependent and lipid peroxidation, has become the recent focus of studies on the occurrence and progress of cardiovascular diseases. However, there are few studies on ferroptosis and IH. Therefore, we aimed to identify and validate ferroptosis-related markers in IH to explore new possibilities for IH diagnosis and treatment. The IH microarray dataset (GSE182291) was downloaded from the Gene Expression Omnibus (GEO) database and ferroptosis-related genes (FRGs) were obtained from the FerrDb databases. The differentially expressed genes (DEGs) were analyzed using the GEO2R. Overlapping was performed to identify the ferroptosis-related DEGs among the DEGs and FRGs. Then, clustering, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) analyses were performed. Subsequently, the hub genes were identified using Cytoscape and hub gene-transcription factors and hub gene-microRNA networks were constructed. Finally, real-time qPCR (RT-qPCR) and immunohistochemistry (IHC) were used to verify the mRNA and protein levels of the hub FRGs in IH. Thirty-four FRGs showing significantly different expression were identified from a total of 1,197 DEGs 2 days after ligation; 31 FRGs were selected from a total of 1,556 DEGs 14 days after ligation. The GO and KEGG analyses revealed that these 34 ferroptosis-related DEGs identified 2 days after ligation were mainly enriched in the basolateral plasma membrane, ferroptosis, lipid and atherosclerosis, and IL-17 signaling pathways. The 31 ferroptosis-related DEGs in endometrial hyperplasia identified 14 days after ligation were mainly enriched in response to oxidative stress, ferroptosis, tumor necrosis factor signaling pathway, and lipid and atherosclerosis. Five hub FRGs (Il1b, Ptgs2, Cybb, Cd44, and Tfrc) were identified using PPI networks; four hub FRGs (Il1b, Ptgs2, Cybb, and Cd44) were validated to be upregulated 2 and 14 days after ligation using RT-qPCR and show significantly different expression 14 days after ligation via IHC. Our findings verify the expression of hub DEGs related to ferroptosis in IH and elucidate the potential relationship between ferroptosis and IH, providing more evidence about the vital role of ferroptosis in IH.

Dataset Information

Carotid artery ligation induced intimal thickening and proliferation is unaffected by ageing.

Publications

Carotid artery ligation induced intimal thickening and proliferation is unaffected by ageing.

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