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  • Review Article
  • Published:

Protein glycosylation in cardiovascular health and disease

Abstract

Protein glycosylation, which involves the attachment of carbohydrates to proteins, is one of the most abundant protein co-translational and post-translational modifications. Advances in technology have substantially increased our knowledge of the biosynthetic pathways involved in protein glycosylation, as well as how changes in glycosylation can affect cell function. In addition, our understanding of the role of protein glycosylation in disease processes is growing, particularly in the context of immune system function, infectious diseases, neurodegeneration and cancer. Several decades ago, cell surface glycoproteins were found to have an important role in regulating ion transport across the cardiac sarcolemma. However, with very few exceptions, our understanding of how changes in protein glycosylation influence cardiovascular (patho)physiology remains remarkably limited. Therefore, in this Review, we aim to provide an overview of N-linked and O-linked protein glycosylation, including intracellular O-linked N-acetylglucosamine protein modification. We discuss our current understanding of how all forms of protein glycosylation contribute to normal cardiovascular function and their roles in cardiovascular disease. Finally, we highlight potential gaps in our knowledge about the effects of protein glycosylation on the heart and vascular system, highlighting areas for future research.

Key points

  • Protein glycosylation is one of the most abundant protein modifications, affecting secreted, extracellular and intracellular proteins.

  • In the cardiovascular system, protein glycosylation regulates diverse homeostatic functions, including contractility, metabolism and transcription, as well as extracellular and intracellular signalling pathways.

  • In the heart, regulation of protein glycosylation contributes to the pathophysiology of heart failure and cardiac hypertrophy and the adverse effects of diabetes mellitus.

  • Dysregulation of protein glycosylation in the vascular system contributes to changes in cell–cell interactions, inflammation and vascular remodelling, including atherosclerosis.

  • Opportunities for future research include the development of humanized mouse models, improved understanding of the regulation of glycogene expression, application of single-cell techniques, and novel approaches to modulate N-glycoforms in vivo.

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Fig. 1: The initial steps in N-glycosylation and O-glycosylation.
Fig. 2: Hexosamine biosynthesis pathway and UDP-GlcNAc synthesis.
Fig. 3: Pathways of UDP-GlcNAc metabolism.
Fig. 4: Summary of the intersection between N-glycans, O-glycans and O-GlcNAcylation in cardiovascular function and disease.

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Acknowledgements

This work was supported in part by the National Institutes of Health (NIH) R21HL152354 and R01HL149354 to J.C.C. and HL153113 to R.P.P. The authors are grateful for the many discussions with A. R. Wende (University of Alabama at Birmingham, AL, USA) during the preparation of the manuscript.

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Chatham, J.C., Patel, R.P. Protein glycosylation in cardiovascular health and disease. Nat Rev Cardiol 21, 525–544 (2024). https://doi.org/10.1038/s41569-024-00998-z

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