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Title: The effects of nitric oxide and nitric oxide-related species on the viability of cell types critical to atherosclerosis : obligatory role of peroxynitrite in cell death
Author: Shaw, Catherine A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Characterisation of the NO-related species generated by the NO donor compounds 1,2,3,4,-oxatriazolium, 5-amino-3-(3,4-dichlorophenyl)-chloride (GEA-3162), diethylamine diazeniumdiolate (DEA/NO), (Z)-1-[2-(2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO), S-nitroso-N-caleryl-D-penicillamine (SNVP) and S-nitrosoglutathione (GSNO), was carried out by a combination of electrochemistry and electron paramagnetic resonance.  Results revealed the diazeniumdiolates, DEA/NO and DETA/NO, spontaneously liberate NO radical in solution. However, GEA-3162 was found to release NO and O2- concomitantly, and therefore, should be regarded as a ONOO- generator. SNVP and GSNO release only small amounts of free NO in solution, however, the mechanism of action of these compounds is likely to also involve the transfer of NO+. The effect of each of these compounds on cell viability was investigated in human monocyte-derived macrophages (Mφ) and an aortic SMC line. In both Mφ and SMC, only the ONOO- generator, GEA-3162, induced cell death. Analysis by flow cytometry revealed GEA-3162 caused cell surface phosphatidylserine exposure characteristic of apoptosis. Furthermore, only GEA-3162 was found to inhibit SMC proliferation, and this occurred independently of 3’,5’-cyclic guanosine monophosphate (cGMP) generation. These results demonstrate that contrary to previous reports, NO per se is incapable of inducing cell death. Finally, apoptotic cell death induced by GEA-3162 in human monocyte-derived Mφ was inhibited by pre-treatment of the cells with a low dose of the NO-releasing compound, DETA/NO. This effect was enhanced by augmenting cGMP levels using a direct guanylate cyclase stimulator, BAY 41-2272. Pre-treatment with DETA/NO failed to protect SMC against GEA-3162-induced cell death, irrespective of inclusion of BAY 41-2272. These results demonstrate that pre-conditioning of Mφ with cGMP protects them against subsequent cell death.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available