A Study of Oxidation and Inflammation using Plaque and Plasma of Vascular Disease Patients
Degree GrantorUniversity of Canterbury
Degree NameMaster of Science
Atherosclerosis is a chronic inflammatory disease leading to the formation of vascular plaques within the major arteries. Vascular plaques consist of a collection of inflammatory cells, extracellular matrix and fibrous material. Advanced plaques are characterised by the formation of necrotic zones often containing free lipid deposits high in cholesterol esters. Though considerable work has been published on the contents of these atherosclerotic plaques very little is known about how the composition varies along the length of the plaque. Nor is it known whether the pterin, 7,8-dihydroneopterin, is released by activated macrophages at levels where it can alter the plaque development through it’s antioxidant activity. Atherosclerotic plaques were removed from patients carotid and femoral arteries during endarectomy surgery and sliced into 3-5 cm sections along the length of the plaque. For each segment the concentrations of neopterin, 7,8-dihydroneopterin, α-tocopherol, TBARS, DOPA, dityrosine, the protein carbonyls α-Aminoadipic semialdehyde (AAS) and γ-glutamic semialdehyde (GGS), 7-ketocholesterol, and cholesterol was measured. Plasma samples were taken from around the sites of coronary plaques during angioplasty procedures and the concentrations of neopterin and 7,8-dihydroneopterin was measured. The oxidant, antioxidant and inflammatory markers analysed in the atherosclerotic plaques showed many strong positive correlations between pairs of markers. The strongest was between α-tocopherol and cholesterol with significant correlations in the majority of plaques analysed. Combined plaque data analysed by dividing the segments up into three zones, pre-bifurcation, bifurcation and post-bifurcation showed that the formation of both protein and lipid oxidation markers were significantly high in the prebifurcation zones while alpha tocopherol was highest in the post-bifurcation zone but failed to reach significants. The pre-bifurcation zone is thought to be associated with a low shear stress level in the plaque and therefore where the oxidants localise. Neopterin levels tended also to be high in the pre-bifurcation zones but failed to reach significants. Pterin levels of as high as 2 μM were recorded suggesting in some regions 7,8- dihydroneopterin levels may reach antioxidant levels. The high variability could suggest that pterin and therefore inflammation within the plaque is a very dynamic and variable process. Overall the data shows that each individual plaque’s composition was relatively unique and variable over the length of the plaque. The plasma samples taken from around coronary plaques showed 7,8-dihydroneopterin levels were on average elevated 3 fold compared to controls with neopterin levels only elevated 2 fold. This suggests 7,8-dihydroneopterin oxidation was not greatly elevated in these patients and the inflammation was an ongoing process. The study shows that 7,8-dihydroneopterin and neopterin production and release is a dynamic process in vascular disease patients. The level of variability though between patients prevents the importance of pterin production on the disease progression to be determined with the current data set.