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Title: Premature senescence, endothelial turnover and accelerated atherosclerosis in SLE : the relationship between circulating endothelial cells, telomere length and lupus factors
Author: Haque, Sahena
ISNI:       0000 0004 2703 7794
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2011
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Systemic lupus erythematosus (SLE) is associated with premature onset of coronary heart disease and endothelial dysfunction. To date the mechanisms underlying this remain unclear. We hypothesise there is premature biological ageing in patients with SLE as evidenced by a reduction in the mean telomere length of PBMC. Premature biological ageing is also evident in the vasculature of patients with SLE and reflected by relatively shortened telomeres of cells involved in vascular repair and regeneration i.e. endothelial progenitor cells (EPC). Furthermore, senescent EPC result in cellular imbalance with a relatively reduced number and/or function of circulating healthy EPC. We studied 200 SLE patients longitudinally over an average of 5.8 (5.2, 6.3) years and demonstrated progression of carotid plaque burden in 17.5%. Baseline traditional CHD risk factors did not influence plaque progression. We measured CD34/CD133+ EPC using flow cytometry in 54 SLE patients and 49 controls in cross-sectional study and demonstrated no significant difference between the groups. We further investigated number and function of EPC by enumerating colony-forming unit (CFU) in culture in 39 SLE patients and 27 controls and demonstrated a significant reduction in CFU number in SLE [median (IQR) CFU 5.7 (2.3, 8.0) in SLE vs. 10.0 (5.7, 15.0) in controls; p= 0.0016] and this difference was particularly marked in those under the age of 40 years [4 (2, 8) vs. 10.5 (7, 19), p= 0.03]. We measured relative telomere length of PBMC in SLE compared to age-matched controls using real-time qPCR in a cross-sectional study and demonstrated a significant reduction in SLE patients [0.97 (0.47, 1.57) and 1.53 (0.82, 2.29), p = P = 0.0008]. Further, telomere length of DNA extracted from CFU after 7 days in culture was quantified in a preliminary study of 5 SLE patients and 5 controls and demonstrated a trend to telomere length reduction in SLE patients. In conclusion there was evidence of significant progression of carotid plaque is in this cohort of female SLE patients. Further there is evidence of abnormal endothelial repair and premature senescence in SLE. Results support the hypothesis that there is a premature senescent phenotype in SLE and as such may present a novel therapeutic target to attenuate the risk of CHD in SLE.
Supervisor: Bruce, Ian ; Alexander, Yvonne ; Day, Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: SLE ; Cardiovascular disease