Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice

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.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.

Investigation of novel metabolites potentially involved in the pathogenesis of coronary heart disease using a UHPLC-QTOF/MS-based metabolomics approach

“…Regarding phosphatidylglycerol (PGs), which a phosphoglycerol moiety occupies a glycerol substitution site, little evidence has been shown on their relationship with CHD, and we were the first to reveal a positive relationship between PG ( 20:3/2:0) and CHD (OR: 3.938; 95% CI: (1.891, 8.204); P = 0.0001) in human plasma. Several previous studies have provided evidence that PGs are significantly increased in atherosclerotic rats 45 , 46 . Elevated levels of PGs were also found in patients with type 2 diabetes and prediabetes 47 .…”

Identification and Validation of Plasma Metabolomics Reveal Potential Biomarkers for Coronary Heart Disease

“…As shown in Figure 6, several plasma LysoPCs and LysoPEs were generated from phosphatidylcholines and phosphatidylethanolamines by the activity of lecithin cholesterol acyltransferase. Low lecithin cholesterol acyltransferase activity has previously been linked to CHD, 9,34,37) although elevated levels of lysophospholipids have been reported to induce oxidative stress in endothelial cells, leading to AS and cardiovascular disease. 38,39) Recently, it has been suggested in some population-based studies that lysophospholipids are inversely associated with CHD and its risk factors.…”

A Prospective Analysis of Circulating Plasma Metabolites Associated with Ovarian Cancer Risk

“…Little work has examined these markers in ovarian cancer development or etiology. Sphingolipids [(SL); including SMs, PCs, PEs, LPCs, LPEs, cholesteryl esters, acylcarnitines] are associated with a series of conditions that may be related to ovarian cancer, including thrombosis in a mouse study (42), myocardial infarction among patients with symptomatic coronary artery disease (43), type I and type II diabetes in human studies (44), diabetic kidney disease in mice (45,46), and airway inflammation and asthma in mouse and human studies (47)(48)(49). Notably, patients with ovarian cancer have the highest incidence of venous thromboembolism of all solid tumor types (50), which is significantly related to higher mortality (51).…”