Abstract
Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models. Metabolites in the sphingomyelin pathway were significantly altered prior to detectable lesion formation and at all subsequent time-points. The cytidine diphosphate-diacylglycerol pathway was up-regulated during stage I of atherosclerosis, while metabolites in the phosphatidylethanolamine and glycosphingolipid pathways were augmented in mice with stage II lesions. These pathways, involving glycerophospholipid and sphingolipid metabolism, were also significantly affected during the course of atherosclerotic progression. Our findings suggest that distinct plasma metabolomic profiles can differentiate the different stages of atherosclerotic progression. This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis.
Highlights
Atherosclerosis is the major underlying cause of most cardiovascular diseases
This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis
The objective of this study was to identify alterations in specific plasma-borne metabolites that are associated with the pathogenesis of atherosclerosis
Summary
Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. Comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive metabolomic techniques were used to investigate atherosclerosis in chow-fed apolipoprotein E-deficient (ApoE−/−) mice at 5, 10 and 15 weeks of age in order to discover novel metabolic pathways and metabolisms associated with early stages of atherosclerotic development and progression. Comprehensive metabolomics involves the global analysis of the metabolome[10,11] This type of approach is capable of revealing novel and unanticipated molecular perturbations as it represents an unbiased examination of the association between the levels of metabolites and their interconnectivity in multiple metabolic pathways, with relation to a phenotype or genotype.
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