Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling

McGarrity, Sarah; Halldórsson, Haraldur; Palsson, Sirus; Johansson, Pär I.; Rolfsson, Óttar

doi:10.3389/fcvm.2016.00010

Cited by 11 publications

(11 citation statements)

References 134 publications

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“…As stated in the Introduction section, the action of neural, hormonal, paracrine or cytokine signaling directly or indirectly modifies cellular metabolic pathways [ 11 , 24 ]. Furthermore, it was shown that even the endothelial mechanoreceptors activity can alter circulating metabolites and may be revealed by metabolomics [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Blood metabolomic fingerprint is distinct in healthy coronary and in stenosing or microvascular ischemic heart disease

et al. 2017

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BackgroundThe endothelium is a key variable in the pathogenesis of atherosclerosis and its complications, particularly coronary artery disease (CAD). Current evidence suggests that the endothelial status can be regarded as an integrated index of individual atherogenic and anti-atherogenic properties, and that the interaction between circulating factors and the arterial wall might be critical for atherogenesis. In organism-level investigations, a functional view is provided by metabolomics, the study of the metabolic profile of small molecules. We sought to verify whether metabolomic analysis can reveal the presence of coronary microenvironment peculiarities associated with distinct manifestations of CAD.MethodsThirty-two coronary blood samples were analyzed using 1H-NMR-based metabolomics. Samples collected from patients with evidence of myocardial ischemia formed the case group, and were further divided into the stenotic-disease (SD) group (N = 13) and absence of stenosis (microvascular disease; “Micro”) group (N = 8); specimens of patients presenting no evidence of ischemic heart disease (dilated cardiomyopathy, valvular diseases) constituted the control group (N = 11).ResultsApplication of an orthogonal partial least squares discriminant analysis (OPLS-DA) model to the entire dataset clearly separated the samples into 3 groups, indicating 3 distinct metabolic fingerprints. Relative to control-group members, Micro patients showed a higher content of 2-hydroxybutirate, alanine, leucine, isoleucine, and N-acetyl groups and lower levels of creatine/phosphocreatine, creatinine, and glucose, whereas SD patients showed higher levels of 3-hydroxybutirate and acetate and a lower content of 2-hydroxybutirate. Moreover, relative to SD patients, Micro patients showed higher levels of 2-hydroxybutirate, alanine, leucine, and N-acetyl groups and lower levels of 3-hydroxybutirate and acetate.ConclusionsSpecific coronary microenvironments are likely associated with distinct development and pathological expression of CAD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1215-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Blood metabolomic fingerprint is distinct in healthy coronary and in stenosing or microvascular ischemic heart disease

et al. 2017

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“…For instance, genome-scale models of cancer metabolism can help us comprehend the complexity of human cancer heterogeneity in relation to substrate preference and therefore expedite the discovery of putative anticancer targets ( 285 ). Genome-scale metabolic models can also be applied to investigate genetic variation in genotype-phenotype interactions and as such can be used to identify metabolic biomarkers and discover treatments based on genetic markers ( 311 ).…”

Section: Future Perspectivesmentioning

confidence: 99%

Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

et al. 2018

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The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability and requirement, is known as metabolic flexibility. In this review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise. The liver, adipose tissue, and muscle govern systemic metabolic flexibility and manage nutrient sensing, uptake, transport, storage, and expenditure by communication via endocrine cues. At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways, which are regulated by key metabolic enzymes and transcription factors, many of which interact closely with the mitochondria. Disrupted metabolic flexibility, or metabolic inflexibility, however, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds, influence metabolic flexibility and will be discussed here. Last, we outline important advances in metabolic flexibility research and discuss medical horizons and translational aspects.

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“…However, these molecular mechanisms still remain to be addressed in details. Recent findings unraveled that endothelial cell biology is driven by a metabolic switch, and metabolic alterations in endothelial cells could mediate angiogenesis and vasculature formation (Eelen et al, 2015; McGarrity et al, 2016). Additionally, as the final downstream products of transcription and translation, metabolites serve as the potential indicators of enzyme activities in pathological and pathophysiological conditions, and metabolomic assay might reveal the overall abnormal metabolic changes in CVD (Kordalewska and Markuszewski, 2015; Würtz et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Mechanisms of Endothelial Cell Protections Between High-Density Lipoprotein and Apolipoprotein A-I Mimetic Peptide

Qian

Huang

et al. 2019

Front. Pharmacol.

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Apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, exhibits anti-atherogenic effects similar to high-density lipoprotein (HDL). However, it remains elusive whether D-4F and HDL share similar molecular mechanisms underlying anti-atherogenic effects and endothelial cell protections. We here compared the metabolic changes in endothelial cells induced by D-4F and HDL against oxidized low-density lipoprotein (ox-LDL), which may be of benefit to understanding the protective mechanisms of HDL and D-4F. Functional assays, including wound healing, transwell migration, and tube formation, were used to evaluate the pro-angiogenic effects of HDL and D-4F. NMR-based metabolomic analysis was employed to explore the protective mechanisms underlying HDL and D-4F. Partial least-squares discriminant analysis (PLS-DA) was performed to assess metabolic profiles, and orthogonal PLS-DA (OPLS-DA) was carried out to identify characteristic metabolites. Moreover, significantly altered metabolic pathways were also analyzed. We found that ox-LDL impaired the migration and tube formation of endothelial cells. Metabolomic analysis showed that ox-LDL triggered oxidative stress, impaired glycolysis, and enhanced glycerophospholipid metabolism. Both HDL and D-4F improved the migration and angiogenesis of endothelial cells, alleviated oxidative stress, and ameliorated disordered glycolysis impaired by ox-LDL. Strikingly, HDL partially attenuated the disturbed glycerophospholipid metabolism, whereas D-4F did not show this effect. In summary, although D-4F shared the similar protective effects with HDL on the migration and angiogenesis of endothelial cells, it could not deduce the molecular mechanisms of HDL completely. Nevertheless, D-4F possesses the potentiality to be exploited as clinically applicable agent for endothelial cell protection and cardiovascular disease treatment.

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Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling

Cited by 11 publications

References 134 publications

Blood metabolomic fingerprint is distinct in healthy coronary and in stenosing or microvascular ischemic heart disease

Blood metabolomic fingerprint is distinct in healthy coronary and in stenosing or microvascular ischemic heart disease

Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

Comparison of Mechanisms of Endothelial Cell Protections Between High-Density Lipoprotein and Apolipoprotein A-I Mimetic Peptide

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