COMPREHENSIVE METABOLOMIC ANALYSIS OF DIABETIC ATHEROSCLEROSIS
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abstract
The prevalence of diabetes mellitus is increasing dramatically worldwide. Approximately three out of four diabetic patients will die of cerebro- and cardiovascular disease (CVD). Atherosclerosis, a chronic inflammatory disease of the medium-large arteries, is the major underlying cause of most CVDs. Despite the established progressive relationship between diabetes and CVD, the molecular mechanisms by which diabetes promotes atherosclerosis are not well understood. This has impeded the development of strategies to block or slow atherogenesis in diabetic patients. The objective of my thesis is to investigate the molecular alterations by which diabetes accelerates the development of atherosclerosis using comprehensive metabolomics techniques.
We first investigated the development and progression of atherosclerosis at the molecular level in apolipoprotein E-deficient mice. We identified specific changes in plasma-borne metabolites that are associated with the pathogenesis and progression of atherosclerosis. In addition, glycerophospholipid and sphingolipid metabolism were found to be the most significantly altered pathways. Using comprehensive metabolomics techniques, we were able to differentiate atherosclerotic plasma metabolome from healthy control and delineate different stages of atherosclerotic progression.
Next, we characterized multiple mouse models of hyperglycemia-induced accelerated atherosclerosis. We showed that the vascular effects of glucosamine supplementation are comparable to streptozotocin-induced and genetically-induced (Ins2Akita) hyperglycemia in terms of lesional glucosamine, endoplasmic reticulum (ER) stress levels and atherosclerotic burden. In addition, we showed that a chemical chaperone (4-phenylbutyric acid) reduces ER stress levels and attenuates accelerated atherogenesis in each of these models. Together these findings support the mechanism involving glucosamine-induced ER stress in hyperglycemia-induced accelerated atherosclerosis.
Lastly, metabolomics techniques were used to investigate the molecular alterations by which hyperglycemia promotes the accelerated development of atherosclerosis in several disease models. The three mouse models induced both unique and common changes in the plasma metabolome. Identification of the commonly altered metabolite features revealed alterations in glycerophospholipid and sphingolipid metabolisms, and key atherosclerosis-associated processes including inflammation and oxidative stress.
Together, we showed that comprehensive metabolomics techniques can be used to identify specific alterations in the metabolome that are associated with a particular disease genotype and phenotype. These data highlight the important roles of the glycerophospholipid and sphingolipid metabolisms in the pathogenesis of atherosclerosis and diabetic atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis.
