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Title: The chemistry of human arterial disease
Author: Gilbert, J. D.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1972
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Abstract:
The work described in this thesis is concerned with the lipids present in the fatty plaques which develop in human arteries during the processes of atherosclerotic degeneration. The variations in concentration and composition of the major lipid classes as the disease progresses have received previous attention. However, other lipids present in smaller quantities have not been investigated in detail, A study of such constituents was undertaken since it seemed possible that some of them might be of significance in the pathology of atherosclerosis. Early attempts to identify the minor steroids which accompany cholesterol in atherosclerotic lesions were hindered, and to some extent vitiated, by the lack of suitable microanalytical techniques. Since accumulation of adequate quantities of lipid necessitated collection and pooling of a large number of arteries, sometimes over a period of years, it is possible that many of the compounds identified were artefacts of the original steroids. In the present study the use of thin-layer chromatography (TLC), gas-liquid chromatograply (GLC) and combined GLC-mass spectrometry (GC-MS) has facilitated rapid and accurate analyses of minor lipids from individual arteries. Lesions from single human aortas, obtained within 24 hours after death, were classified according to the WHO convention. Following extraction, the lipids were fractionated by column chromatography. The extraction and chromatographic procedures were performed expeditiously to minimise artefact formation. By repeated TLC on modified layers 5alpha-cholestan-3beta-ol (cholestanol) was isolated from both sterol and sterol ester fractions. The concentration of this compound in severely diseased tissue was estimated by GLC, and found to be considerably less than had been reported by some earlier workers. Since recent publications suggest that the aortal concentration of cholestanol does not differ markedly from those of other tissues, and no relationship appears to exist between its aortal content and degree of atherosclerosis, it seems unlikely that this compound plays any significant role in the development of the disease. 26-Hydroxycholesterol is known to occur in both normal and diseased aortas. Although its function is unknown, the increased concentrations found in lesions suggest a possible relationship between this sterol and atherosclerosis. The present work demonstrates the occurrence in both early and advanced lesions of a diesterified form of this sterol. The distribution of the fatty acids of this unique type of ester is markedly different from that of the cholesterol esters. Whereas arterial cholesterol esters appear to be derived mainly from blood, the distinctive fatty acids of 26-hydroxycholesterol diesters may reflect a different origin for these constituents. Previous work in Glasgow had demonstrated the presence in extracts of severely diseased aortas of a group of esters consisting largely of cholesterol esterified with 9- and 13-hydroxyoctadecadienoic acids, A survey was undertaken in an attempt to relate the quantities of these hydroxy-esters with the severity of atherosclerosis. The quantities of the hydroxy-acids derived from these esters were determined by GLC, None of the hydroxy-esters were detected in the earliest lesions, but considerable amounts were isolated from those representing more advanced atherosclerosis. These results establish what may be an important distinction between early and advanced lesions. In order to assist the identification of other oxygenated sterol esters in diseased tissue, a study was made of the oxidation products of cholesteryl linoleate. Those derived from hydroperoxides produced by autoxidation and photo-oxygenation of cholesteryl linoleate were dissimilar, as expected from published data on other linoleic acid derivatives. The development of improved techniques enabled the identification in arterial extracts of hydroperoxy- and keto-esters similar to those derived from autoxidised cholesteryl linoleate. It seems probable that the keto- and hydroxy-esters found in tissue are derived from the corresponding hydroperoxides. The pathogenic character of lipid hydroperoxides is well established, and the production of hydroxy compounds has been shown to be a possible route for "detoxification". The present findings may reflect such a process. However, the full significance of oxygenated derivatives of cholesteryl linoleate to the pathogenesis of atherosclerosis requires to be ascertained. In particular, the origin of the hydroperoxides must be clearly established. At present it is not known whether these substances occur in arteries prior to death, or accumulate in the interval between death and analysis. Examination of tissues obtained during surgery may resolve this problem. The metabolic processes whereby hydroperoxides arise and are removed are being studied in homogenates of human and animal aortas, and a method for the qualitative assessment of hydroperoxide toxicity in vivo is being developed. Whether these compounds arise by an enzymic or non-stereospecific oxidation should be determinable by resolution of the enantiomeric hydroperoxide derivatives.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.795734  DOI: Not available
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