Role of the Haem Oxygenase Pathway in Protection against Vascular Dysfunction

Impairment of vascular function and tissue injury after ischaemic events is a well-known pathophysiological phenomenon. Enhanced oxidative stress by free radicals appears to be a major contributor to the ischaemic episode which can occur either by progression of a disease state (atherosclerosis or angina pectoris) or after surgical intervention (organ transplantation). As a new approach for the preservation of vascular function after ischaemia, one line of research is considering the exposure of tissues to agents or treatments that lead to the stimulation of a number of natural intracellular defense mechanisms. This phenomenon is generally known as the “stress response” and invariably involves the de-novo¬ synthesis of inducible proteins known as heat shock proteins. One such mechanism is the induction of the haem oxygenase (HO) pathway. Haem oxygenase is the mammalian enzyme which degrades haem to the antioxidant biliverdin and carbon monoxide (CO) releasing ferric (Fe3+) iron. Biliverdin is rapidly converted to another potent antioxidant, bilirubin, by the cytosolic enzyme biliverdin reductase. Of the three known isozymes, the inducible isoform (HO-1) has been proposed to act as an effective system to counteract oxidant-mediated cell injury since it is extremely sensitive to up-regulation in a variety of mammalian tissues. The aim of this research project is to investigate the role of this potentially beneficial enzyme system in ameliorating vascular dysfunction following stressful insults. In particular, 1) the way in which the HO-1 gene is modulated; 2) the role of CO and bilirubin as important effector molecules and 3) the dynamics of the HO-1/bilirubin pathway are examined.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

UCL University College London

Year dc:date.issued

2000

Author dc:creator

• Clark, James

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/8f24a49c-c470-4ee3-8bde-161871203918

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/8f24a49c-c470-4ee3-8bde-161871203918