AUTHOR=Cairns Megan , Joseph Danzil , Essop M. Faadiel TITLE=The dual role of the hexosamine biosynthetic pathway in cardiac physiology and pathophysiology JOURNAL=Frontiers in Endocrinology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.984342 DOI=10.3389/fendo.2022.984342 ISSN=1664-2392 ABSTRACT=

The heart is a highly metabolic organ with extensive energy demands and hence relies on numerous fuel substrates including fatty acids and glucose. However, oxidative stress is a natural by-product of metabolism that, in excess, can contribute towards DNA damage and poly-ADP-ribose polymerase activation. This activation inhibits key glycolytic enzymes, subsequently shunting glycolytic intermediates into non-oxidative glucose pathways such as the hexosamine biosynthetic pathway (HBP). In this review we provide evidence supporting the dual role of the HBP, i.e. playing a unique role in cardiac physiology and pathophysiology where acute upregulation confers cardioprotection while chronic activation contributes to the onset and progression of cardio-metabolic diseases such as diabetes, hypertrophy, ischemic heart disease, and heart failure. Thus although the HBP has emerged as a novel therapeutic target for such conditions, proposed interventions need to be applied in a context- and pathology-specific manner to avoid any potential drawbacks of relatively low cardiac HBP activity.