Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692499
Title: Mitochondrial reactive oxygen species signalling and vascular smooth muscle cell senescence
Author: Sanusi, Morufat Olayide Abisola
ISNI:       0000 0004 5918 9688
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2016
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Abstract:
Ageing is a risk factor for the development of cardiovascular disease. In particular, senescent vascular smooth muscle cells (VSMCs) have been observed within atherosclerotic plaques. Oxidants are widely implicated in vascular ageing and cardiovascular disease with evidence of oxidative stress in cells undergoing senescence. Our previous data showed that Angiotensin II caused stress induced premature senescence (SIPS) in primary human VSMC via oxidant generation. Prevention of senescence with a mitochondria targeted antioxidant, Mito-TEMPO, suggested the mechanism was dependent on mitochondrial superoxide. The current study aimed to investigate if modulation of mitochondrial reactive oxygen species signalling is a general mechanism for senescence induction in human VSMC. The electron transport chain inhibitors Antimycin A and rotenone and the mitochondrial redox cycler, MitoParaquat all stimulated SIPS in VSMC. Interestingly, Antimycin A and rotenone also lead to a reduction in overall H₂O₂ levels suggesting a possible protective mechanism and highlighting the complexity of the signalling mechanism involving mitochondrial oxidants. qPCR Analysis suggested that changes in antioxidant gene expression do not account for the reduction in peroxide levels. Although there was no evidence that Angiotensin II induced senescence in human coronary artery SMC, there was evidence for enhanced mitochondrial hydrogen peroxide production. Senescent cells acquire a senescence associated secretory phenotype (SASP). To determine the composition of VSMC SASP, the tryptically digested secretome of conditioned media was analysed by LC-MS/MS. Bioinformatic analysis identified the NRF2-mediated oxidative stress response pathway and several endogenous antioxidants as amongst the affected responses in the aged VSMC secretome. These new data suggest that senescent VSMC produce a SASP that has multiple effects on neighbouring cell types including the induction of cell senescence and death; but also elements that might serve to preserve cell integrity and function and may limit the expression of a pro-inflammatory phenotype.
Supervisor: Herbert, Karl ; Goodall, Alison Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.692499  DOI: Not available
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