The reactive nitrogen species (RNS) nitric oxide (NO), nitroxyl anion (NO") and nitrosonium cation (NO+), modulate a myriad of biological processes. The microsomal haem oxygenases (HO-1, HO-2 and HO-3) oxidatively catabolise haem to bilirubin, carbon monoxide (CO) and ferrous iron (Fe2+). Sensitivity of the inducible isoform (HO-1) to a variety of inducers has identified HO-1 as an effective endogenous cytoprotectant against oxidative stress. Although nitrosative stimuli can enhance HO-1 expression, little is known about the biochemistry and mechanisms of this response. This Thesis examines a number of aspects related to HO-1 and nitrosative stimuli in cardiac cells, including: 1. induction by NO" 2. the biochemistry of NOVNO-mediated induction of HO-1 3. identification of a possible mechanism for the activation of HO-1 by NO congeners 4. the antinitrosative potential of bilirubin and 5. the potential of glyceryl trinitrate (GTN), a clinically used NO donor, to activate the haem oxygenase pathway. These different aspects of HO-1 were addressed using biochemical, molecular biology and cell culture techniques. The results indicate that NO", in analogy with other RNS, is a potent inducer of haem oxygenase activity and HO-1 mRNA and protein expression. A proposed mechanism for this response is modulation of thiol groups within redox-sensitive transcription factors. An antinitrosative and HO-1 inducing capacity was identified for bilirubin and GTN, respectively. Collectively, these findings suggest that the haem oxygenase pathway can act both as a sensor to, and target of, redox based mechanisms involving RNS, and extend our knowledge on the biological function of HO-1 in response to nitrosative stress.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:421047 |
| Date | January 2005 |
| Creators | Naughton, Patrick |
| 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/1444863/ |
Page generated in 0.0167 seconds