Haemoglobin and nitric oxide (NO) strongly induce the stress protein haem oxygenase-1 (HO-1), which degrades haem to carbon monoxide (CO), a signalling and vasoactive molecule, the anti-oxidant biliverdin (BV) and iron. Raised HO-1 levels have been detected in the endothelium and kidneys of animals, as well as leukocytes of patients, suffering from sickle cell disease (SCD). A genetic mutation of haemoglobin causes SCD, pathologic symptoms of which include vaso-occlusive crises and high concentrations of free haemoglobin liberated during red blood cell haemolysis. Although HO-1 and its products have been linked to SCD, their potential role in this condition has not been examined. The work of this thesis aimed to: 1) investigate the interaction of haemoglobin and NO in modulating endothelial HO-1 expression 2) examine the effect of human sickle cell blood on HO-1 induction and vascular function and 3) assess the role of HO-1 and its products on sickle cell blood adhesion and regulation of vessel contractility. Experiments were performed using a combination of in vitro (cell culture and biochemical assays) and ex-vivo (isolated aortic rings) models. The results of the study indicated that NO synergises with haemoglobin to amplify HO-1 expression and haem incorporation by endothelial cells, suggesting that similar mechanisms might contribute to changes in vascular function occurring in haemolytic disorders. It was also found that sickle cell blood induces haem oxygenase to a greater extent than normal blood, an effect which is magnified under hypoxia. The increased haem oxygenase elicited by sickle cell blood depends on the time elapsed since the last vaso-occlusive crisis experienced by the patient. Finally, CO and BV diminish sickle blood adhesion to the endothelium and sickle blood can alter CO-mediated vessel relaxation. These findings support a functional role for the HO-1 pathway in SCD and may help to identify therapeutic strategies to counteract the vascular damage caused by SCD.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:500150 |
| Date | January 2008 |
| Creators | Bains, Sandip Kaur |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1444103/ |
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