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Protein O-GlcNAcylation in cardiovascular diseases

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Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart

Darnel Prakoso et al.

Summary: Elevated protein O-GlcNAc modification is observed in diabetic human myocardium, and selectively targeting cardiac protein O-GlcNAcylation may offer a new therapeutic approach for diabetes-induced heart failure. In non-diabetic mice, rAAV6-OGT impairs LV diastolic function and induces maladaptive cardiac remodelling, while rAAV6-OGA rescues LV diastolic function and adverse cardiac remodelling in diabetic mice.

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John C. Chatham et al.

Summary: The discovery of O-GlcNAcylation in the mid-1980s challenged the conventional notion of glycosylation and its impact on cellular functions. Dysregulation in O-GlcNAc cycling has been implicated in the progression of various diseases.

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Truncation of the TPR domain of OGT alters substrate and glycosite selection

Daniel H. Ramirez et al.

Summary: Iterative truncations to the TPR domain of OGT affect the subcellular localization of OGT and the selection of substrates and glycosites. Different TPR isoforms result in varied modifications of O-GlcNAc on proteins, with the first four TPRs having the broadest substrate scope.

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Cardiomyocyte protein O-GlcNAcylation is regulated by GFAT1 not GFAT2

Adam A. Nabeebaccus et al.

Summary: In response to cardiac injury, the hexosamine biosynthesis pathway (HBP) plays a significant role, with glutamine-fructose amidotransferase (GFAT) being a key enzyme in the pathway. GFAT1 is primarily expressed in cardiac myocytes, while GFAT2 is mainly expressed in cardiac fibroblasts. Knockdown of GFPT1 in cardiac cells resulted in reduced HBP activity. Cell-specific isoform expression may have different effects on cell function, which should be considered in studies of HBP and GFAT functions in the heart.

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Analytical and Biochemical Perspectives of Protein O-GlcNAcylation

Junfeng Ma et al.

Summary: Protein O-GlcNAcylation is an important post-translational modification that functions as a nutrient sensor and plays key roles in biochemical processes. Research on this modification has made significant progress in characterizing the components of O-GlcNAc cycling, biochemical properties of enzymes, and potential therapeutic applications. Challenges and solutions for future research in this field are also discussed.

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Regulation of O-Linked N-Acetyl Glucosamine Transferase (OGT) through E6 Stimulation of the Ubiquitin Ligase Activity of E6AP

Kangli Peng et al.

Summary: OGT, a glycosyltransferase, can be ubiquitinated and degraded by E3 ubiquitin ligase E6AP, resulting in the suppression of O-GlcNAc modification of OGT substrates in cells. This study establishes a new mechanism of OGT regulation by the ubiquitin-proteasome system.

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A cold-stress-inducible PERK/OGT axis controls TOM70-assisted mitochondrial protein import and cristae formation

Pedro Latorre-Muro et al.

Summary: The study reveals a PERK-OGT-TOM70 axis that regulates mitochondrial protein import and cristae formation, ultimately increasing cell respiration. This mechanism also affects mitochondrial structure and plays a crucial role in cellular adaptations to stress conditions.

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Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death

Priya Umapathi et al.

Summary: Excessive O-GlcNAcylation contributes to cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated, and attenuation of O-GlcNAcylation is beneficial against pressure overload-induced pathologic remodeling and heart failure.

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Revascularisation of type 2 diabetics with coronary artery disease: Insights and therapeutic targeting of O-GlcNAcylation

Israel O. Bolanle et al.

Summary: Coronary artery bypass graft (CABG) using autologous saphenous vein remains the gold standard for treating CAD patients, but those with T2DM are at higher risk of graft failure. Protein O-GlcNAcylation has emerged as a key mechanism in the pathogenesis of vein graft failure in T2DM, providing potential therapeutic targets for new drug development.

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Blocked O-GlcNAc cycling alters mitochondrial morphology, function, and mass

Elizabeth O. Akinbiyi et al.

Summary: This study evaluated the impact of O-GlcNAcylation on mitochondrial dynamics and function, revealing that in a high O-GlcNAcylation environment, mitochondria decrease in size but increase in number, showing comparable mitochondrial oxidative phosphorylation activity. Additionally, the study found that O-GlcNAcylation affects mitochondrial dynamics and the activity of electron transport chain complexes.

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Cardiac hypertrophy drives PGC-1α suppression associated with enhanced O-glycosylation

Robert E. Brainard et al.

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Feedback Regulation of O-GlcNAc Transferase through Translation Control to Maintain Intracellular O-GlcNAc Homeostasis

Chia-Hung Lin et al.

Summary: This study investigates the O-GlcNAc-feedback regulation of OGT and OGA expression in lung cancer cells, revealing that OGA expression is regulated at the mRNA level while OGT expression is controlled through translation. The research also highlights the important role of 4E-BP1 in maintaining intracellular O-GlcNAc levels homeostasis.

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With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension

Sasha Z. Prisco et al.

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Protein O-GlcNAcylation in the heart

Yann Huey Ng et al.

Summary: O-GlcNAcylation is a crucial post-translational modification in the heart, with both harmful and beneficial effects on cardiovascular function. There is a complex interaction between O-GlcNAcylation and phosphorylation in cardiac cells, and this modification also indirectly affects transcription factors and downstream signaling pathways.

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Hyper-O-GlcNAcylation impairs insulin response against reperfusion-induced myocardial injury and arrhythmias in obesity

Lingyan Jin et al.

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O-GlcNAcylation contributes to intermittent hypoxia-associated vascular dysfunction via modulation of MAPKs but not CaMKII pathways

Xueling Guo et al.

Summary: This study demonstrates that O-GlcNAcylation plays a regulatory role in IH-induced vascular dysfunction by modulating the MAPK signaling pathways rather than the CaMKII pathway.

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Hypoxic acclimation improves cardiac redox homeostasis and protects heart against ischemia-reperfusion injury through upregulation of O-GlcNAcylation

Wei Ou et al.

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