N-glycosylation signature and its relevance in cardiovascular immunometabolism

Glycosylation is a post-translational modification in which complex, branched carbohydrates (glycans) are covalently attached to proteins or lipids. Asparagine-link protein (N-) glycosylation is among the most common types of glycosylation. This process is essential for many biological and cellular functions, and impaired N-glycosylation has been widely implicated in inflammation and cardiovascular diseases. Different technical approaches have been used to increase the coverage of the N-glycome, revealing a high level of complexity of glycans, regarding their structure and attachment site on a protein. In this context, new insights from genomic studies have revealed a genetic regulation of glycosylation, linking genetic variants to total plasma N-glycosylation and N-glycosylation of immunoglobulin G (IgG). In addition, RNAseq approaches have revealed a degree of transcriptional regulation for the glycoenzymes involved in glycan structure. However, our understanding of the association between cardiovascular risk and glycosylation, determined by a complex overlay of genetic and environmental factors, remains limited. Mostly, plasma N-glycosylation profiling in different human cohorts or experimental investigations of specific enzyme functions in models of atherosclerosis have been reported. Most of the uncovered glycosylation associations with pathological mechanisms revolve around the recruitment of inflammatory cells to the vessel wall and lipoprotein metabolism. This review aims to summarise insights from omics studies into the immune and metabolic regulation of N-glycosylation and its association with cardiovascular and metabolic disease risk and to provide mechanistic insights from experimental models.

The combination of emerging techniques for glycomics and glycoproteomics with already achieved omics approaches to map the transcriptomic, epigenomic, and metabolomic profile at single-cell resolution will deepen our understanding of the molecular regulation of glycosylation as well as identify novel biomarkers and targets for cardiovascular disease prevention and treatment.