Date of Award
Program or Major
Doctor of Philosophy
Alterations and accumulations of glycosaminoglycans (GAG) and lipids are prominent features in atherosclerotic lesions. Lysosomes are essential for cellular catabolism and are known to be altered in advanced atheroslcerotic lesions; however, their involvement in spontaneous atherogenesis or lesion progression is unclear. Estrogens have been reported to interact with lysosomes and are thought to provide a "protective" effect against development of atherosclerotic lesions. Analysis of lysosomes from sites predisposed to lesions, as well as consideration of the effects of estrogens on lysosomes at different stages of lesion development, may provide insight into biochemical mechanisms of spontaneous atherogenesis and lesion progression. Simultaneous analysis of lesion-resistant aortic segments provides a control for differentiating between aging processes and lesion development.
Lysosomal fragility and marker enzyme activities, N-acetyl-B-hexosaminidase (NAHase) and acid phosphatase (APase), were measured in subcellular fractions from upper thoracic aortas (lesion-resistant areas) and celiac bifurcations (site predisposed to lesions) from atherosclerosis-susceptible White Carneau (WC) and atherosclerosis-resistant Show Racer (SR) pigeons at 1 day, 6 weeks, 6 months, and 6 years of age. Isolated arterial segments were also incubated with 17B-estradiol at physiological temperatures to determine the effect on lysosomal fragility and enzyme activities.
Lysosomal enzyme activities and protein yields in both aortic sites from 6 week old WC pigeons were higher than in corresponding SR; thus, turnover rates of cellular components would appear higher in the WC than in the SR. However, the lysosomes from 6 week old WC aortas also appeared more fragile than lysosomes from SR aortas. Sine this is prior to appreciable GAG and lipid accumulation in WC celiac sites, excessive release of lysosomal enzymes and/or greater activities of these enzymes may cause alterations in connective tissue matrix and mitochondrial function which are associated with lipid accumulation during atherogenesis in the WC. The increased lysosomal fragility may also deplete the cell's vacuole system of acid hydrolases therefore decreasing catablism of intracellular components and endocytosed material eg. lipid.
Estrogen treatment increased APase activity and protein yield in the "lysosomal" fraction of 6 week old birds suggesting an increase in number of lysosomes which may aid cellular catabolism and explain the reported estrogen "protection" against lesion development in WC.
Soluble NAHase activity increased in the WC celiac segment by 6 years of age and may explain the altered GAG profiles which occur during atherosclerotic lesion progression.
Since the greater lysosomal enzyme activities, protein yields and membrane fragility in the WC occur at both tissues sites, a genetic mechanism is indicated. In the WC celiac segment higher lysosomal enzyme activities, protein yields and membrane fragility appear augmented by local factors, and may play a major role in spontaneous atherogenesis.
HOUGH, JANE LINSCOTT, "INVOLVEMENT OF LYSOSOMES IN SPONTANEOUS ATHEROGENESIS AND THE EFFECTS OF ESTROGENS" (1981). Doctoral Dissertations. 1283.