Abstract
High-throughput biochemical profiling has led to a requirement for advanced data interpretation techniques capable of integrating the analysis of gene, protein, and metabolic profiles to shed light on genotype–phenotype relationships. Herein, we consider the current state of knowledge of endothelial cell (EC) metabolism and its connections to cardiovascular disease (CVD) and explore the use of genome-scale metabolic models (GEMs) for integrating metabolic and genomic data. GEMs combine gene expression and metabolic data acting as frameworks for their analysis and, ultimately, afford mechanistic understanding of how genetic variation impacts metabolism. We demonstrate how GEMs can be used to investigate CVD-related genetic variation, drug resistance mechanisms, and novel metabolic pathways in ECs. The application of GEMs in personalized medicine is also highlighted. Particularly, we focus on the potential of GEMs to identify metabolic biomarkers of endothelial dysfunction and to discover methods of stratifying treatments for CVDs based on individual genetic markers. Recent advances in systems biology methodology, and how these methodologies can be applied to understand EC metabolism in both health and disease, are thus highlighted.
Highlights
Cardiovascular disease (CVD) includes acute and chronic conditions, such as stroke and coronary heart disease [1]
In the past 5 years, multiple applications of genome-scale metabolic models (GEMs) descriptive of human metabolism have materialized that may contribute to the understanding of how genetic and environmental factors collectively contribute to CVD disease phenotypes when applied to endothelial metabolic research
Computational techniques exist that predict the pathways likely to be responsible for differences between two metabolic states, identifying these differences allows reactions, linked to genes in a GEM, to be selected as drug targets, for example in hepatocellular carcinoma and Alzheimer’s, or metabolites to be identified as potential biomarkers for example for drug resistance in ovarian cancer [100, 106,107,108]
Summary
Cardiovascular disease (CVD) includes acute and chronic conditions, such as stroke and coronary heart disease [1]. The endothelium is the single cell layer that lines blood vessels and lymphatic system and its dysfunction contributes to the development of CVD [4, 5]. A vascular surface that normally is thromboresistant, antiinflammatory, vasodilatory, and antiproliferative can turn into a surface that is thrombogenic, proinflammatory, vasoconstricive, and stimulatory of smooth muscle cell proliferation. Often this change is reactive and transient restoring vascular homeostasis. We consider endothelial metabolic alterations, their contribution to endothelial dysfunction, and integrated analysis of this information with genome-scale metabolic models (GEMs) to advance personalized health care
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