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Title: Analysis of inflammatory phenotype in human endothelial cell senescence
Author: Nouman, Sadaf
ISNI:       0000 0004 7656 0661
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Ageing is the major risk factor for the development of cardiovascular diseases. Endothelial cells play a major role in the normal physiology of vessel wall. Endothelial dysfunction contributes to the development of cardiovascular diseases. In particular, the presence of senescent endothelial cells in the atherosclerotic plaque. Association of senescent endothelial cells in the development of endothelial dysfunction is not clear. This thesis was aimed to investigate the phenotype of senescent (SIPS and REPS) HUVECs and perhaps develop their markers In vitro models of senescent endothelial cell were developed i.e. SIPS and REPS. Genes identified from previous transcriptomics data analysis, for the first time, notably included CST1, LRRC17 and CRTAC1 as differentially expressed in senescent HUVEC. Their expression was validated by quantitative PCR but the gene product of CST1, cystatin SN, was not identified in Western blotting. Subsequent bioinformatics re-analysis of differentially expressed genes described molecular pathways, molecular functions and diseases that were affected in senescent HUVECs. Senescent cells are presented with senescent associated secretory phenotype (SASP). Perhaps the pro-inflammatory factors in SASP contribute to the endothelial dysfunction. Characterisation of the secretome from senescent endothelial cells using mass spectrometry did not identify pro-inflammatory factors. Moreover, SASP from senescent HUVECs did not potentiate the binding of monocytic cells to endothelial monolayers. However, functional assays confirmed increased adhesion of monocytes to senescent HUVECs in both static and flow-based cell models in vitro. Further investigation of candidate genes involved in the adhesion of monocytes to endothelial cells in these scenarios, identified E-selectin and CD44 as potential mediators. Taken together, these new data suggest that senescent endothelial cells might represent a pro-inflammatory phenotype via expressing adhesion molecules that could recruit inflammatory cells to sites of vascular damage or endothelial dysfunction.
Supervisor: Herbert, Karl ; Macip, Salvador Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available