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Title: Transcriptional regulation of cystathionine-γ-lyase in endothelial cells by NADPH oxidase 4-dependent signalling
Author: Mistry, Rajesh Kumar
ISNI:       0000 0004 5372 0597
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Hypertension is a major risk factor implicated in the development of cardiovascular disease and is often associated with endothelial dysfunction. Studies have shown that hydrogen sulfide (H2S) elicits beneficial actions in the regulation of vascular homeostasis where it modulates improved vascular tone. Evidence suggests that reactive oxygen species (ROS) may regulate the expression and activation of H2S-generating enzymes within the vascular endothelium. Endothelial NADPH oxidase 4 (Nox4) is an enzyme that specifically generates the ROS, hydrogen peroxide (H2O2). It was therefore hypothesised that Nox4-derived ROS may be involved in the regulation of H2S generation in the endothelium. Here it was shown, in human umbilical vein endothelial cells (HUVECs), that Nox4 regulates the expression of a major H2S producing enzyme, Cystathionine γ-lyase (CSE) at the mRNA and protein level. Furthermore, this was shown to be dependent on the direct binding of the Activating Transcription Factor 4 (ATF4) to an intronic enhancer region of the CSE gene. Nox4 was also demonstrated to regulate CSE expression through the haem-regulated inhibitor kinase (HRI)/eukaryotic translation initiation factor 2α (eIF2α)/ATF4 signalling module. Finally, CSE mRNA and protein expression were increased in endothelial cells isolated from endothelial-specific Nox4 transgenic mice (eNox4 Tg) and using wire myography it was demonstrated that eNox4 Tg mouse aortae exhibit a hypo-contractile phenotype in response to phenylephrine, compared to Wild type (WT) littermates. This phenotype was ablated when vessels were incubated with the CSE inhibitor, Propargyl-glycine (PPG). To conclude, these data demonstrate a novel role for Nox4 in the regulation of CSE and hence vascular tone in endothelial cells.
Supervisor: Brewer, Alison ; Eaton, Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available