ArticleCell metabolism2025
Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
Article in Cell metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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Who cites it
8 citing papers in PubMed.
- OGT-mediated O-GlcNAcylation Protects Against Myocardial Ischemia-Reperfusion Injury via Targeting MG53.Applied biochemistry and biotechnology · 2026Article
- A Unique Intercellular Feedforward Loop From HK1 to TGF-β1 Promotes the Progression of Hepatocellular Carcinoma.Journal of extracellular vesicles · 2026Article
- Metabo-epigenetic circuits of heart failure: chromatin-modifying enzymes as determinants of metabolic plasticity.EMBO molecular medicine · 2026Review
- O-GlcNAcylation in diabetic cardiac remodeling and a proposed endothelial-macrophage-fibroblast network.Frontiers in immunology · 2026Review
- The mechanism and treatment of protein acylation modification in cardiovascular disease: a narrative review.Frontiers in pharmacology · 2026Review
- Is Type 2 Diabetes a Modifiable Risk Factor for the Evolution and Progression of Heart Failure With a Preserved Ejection Fraction?Journal of the American College of Cardiology · 2025Review
- Review
- Mitochondrial dysfunction as a therapeutic nexus in HFpEF: therapeutic target and pharmacological advances.Frontiers in pharmacology · 2025Review
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.
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