Naughton, P.; (2005) Regulation of haem oxygenase-1 nitrosative stress in cardiac cells. Doctoral thesis , University of London.

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Abstract

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.

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