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.Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide 1,2 . Risk factors of CVD include obesity, dyslipidemia, stress, smoking, hypertension and diabetes mellitus 3 . The major underlying cause of most CVD is atherosclerosis, which is a multifactorial and progressive disease of the medium-large arteries 4 . Atherosclerosis is characterized by the accumulation of lipids and inflammatory factors in the arterial walls. Despite recent advances, the molecular mechanism(s) underlying the pathogenesis and progression of atherosclerosis are still not completely understood [5][6][7] . This has complicated the diagnosis, treatment and prevention of atherosclerosis-related diseases.Metabolomics, which is the study of small molecules, offers a novel approach to investigate disease mechanisms and identify disease biomarkers, as it is capable of providing a global snapshot of the dynamic intracellular changes associated with a particular physiological or pathological state 8,9 . Moreover, the levels of metabolites can more accurately reflect the functional status of an organism compared to the other 'omics' studies, such as genomics or proteomics, because metabolic fluxes are regulated not only by gene expression, but also by environmental stresses 10 . Therefore, the status of specific metabolite levels is a critical indicator of human health or disease.

A therosclerosis is the main underlying pathology of cardiovascular disease, which accounts for the majority of deaths in developed nations.1 Myeloid lineage cells are critical mediators in the development of atherosclerosis and account for the majority of a lesion's cellular bulk.2 Within the atherosclerotic lesion, macrophages phagocytose modified lipid particles becoming lipid engorged foam cells. Foam cells exacerbate disease progression through the secretion of proinflammatory cytokines and growth factors. In advanced lesions, foam cells undergo apoptosis leading to the formation of a lipid-rich, acellular, and highly thrombotic necrotic core. The underlying molecular mechanisms that regulate myeloid cell behavior during atherosclerosis remain poorly defined.Increasing evidence suggests that myeloid cell subpopulations are heterogeneous and have distinctive phenotypes that play unique roles in disease states. Macrophages are often broadly classified as having a classical (M1) or an alternative (M2) phenotype. M1 macrophages, elicited by toll-like receptor or interferon-γ receptor stimulation, are the most prominent macrophages at sites of inflammation and exacerbate the inflammatory response through the secretion of proinflammatory cytokines and chemoatractants.3,4 M1 macrophages promote atherosclerotic lesion development and complexity.5-7 M2 macrophages patrol tissue, perform reparative and immunoregulatory functions, efferocytose debris, and are antiatherogenic. 3,4,8 Other macrophage subtypes have been identified in atherosclerotic lesions, including M4, Mox, and Mhem; however, their roles are less well characterized. 3,5,9,10 Our understanding of the cellular signaling networks that regulate macrophage polarization in the context of atherosclerosis and the relative contribution of each phenotype to the progression and development of atherosclerosis is limited.Glycogen synthase kinase (GSK)-3 α and β are homologous serine/threonine kinases encoded by separate genes. 11GSK3α and GSK3β share 98% amino acid homology within their kinase domain but only 36% homology in the C-terminal domain. GSK3α (51 kDa) is 5 kDa larger than GSK3β (46 kDa) because of an N-terminal glycine-rich domain with an © 2015 American Heart Association, Inc. Objective-Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue-and homolog-specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3α or GSK3β on atherosclerosis in low-density lipoprotein receptor (LDLR) −/− mice. Approach and Results-We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR −/− mice, and mice were fed a high-fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid ...

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