Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/28528
Title: Investigations on arsenite induced premature senescence in human vascular endothelial cells
Authors: Malik, Qudsia
Supervisors: Herbert, Karl
Williams, Bryan
Award date: 1-Dec-2013
Presented at: University of Leicester
Abstract: Chronic exposure of humans to arsenic contaminated drinking water promotes the development of atherosclerosis and is a problem in many countries worldwide. The pathogenic mechanisms are ill-defined, although arsenite-induced endothelial dysfunction has been hypothesised. Ageing is a major risk factor for atherosclerosis and aged (senescent) endothelial cells have been observed in human and experimental atherosclerosis, including in people with arsenicosis. Senescence is a cellular state of irreversible growth arrest, the accumulation of such cells could contribute to the development of age-related diseases. The aim of this thesis was to determine whether arsenite induced premature senescence in human vascular endothelial cells in vitro and whether the mechanisms involved reactive oxygen species-mediated cellular damage. Since mitochondria are a major source of cellular oxidants, studies to determine whether mitochondria were the primary targets for arsenic toxicity were carried out. At sub-cytotoxic concentrations, using a cell culture model, arsenite caused stressinduced premature senescence in HUVECs which was quantitatively similar to induction of senescence by low levels of serial peroxide. Microarray-based transcriptomics revealed that antioxidant responses, including Nrf2-oxidative stress response pathway and metallothioneins, were upregulated in HUVECs treated with subcytotoxic arsenite concentrations supporting arsenite-induced oxidative stress as a possible mechanism. This was accompanied by an increase in nuclear DNA damage observed using the Comet assay. Although no statistically significant effects on mitochondrial biogenesis or mtDNA damage were seen using qPCR, analysis by extracellular flux analyzer revealed a decline in mitochondrial function, specifically the mitochondrial reserve capacity. These findings cast serious doubt that mitochondria are the primary targets of arsenite in endothelial cells, with the oxidative stress occurring through cytoplasmic sources and leading to cellular damage. This forms a possible mechanism for the observed premature senescence in endothelial cells due to arsenite which is linked with the process of atherosclerosis in humans.
Links: http://hdl.handle.net/2381/28528
Type: Thesis
Level: Doctoral
Qualification: PhD
Sponsors / Funders: Medical Research Council
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Cardiovascular Sciences
Leicester Theses

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2013MalikQPhD.pdfThesis26.86 MBAdobe PDFView/Open
2013MalikQPhD_Appendix_1.xlsxAppendix 1 - Microarray Raw Data14.91 MBUnknownView/Open
2013MalikQPhD_Appendix_2.xlsxAppendix 2 - Microarray Significant Data452.02 kBUnknownView/Open


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