Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice

Cabrera, Jody Tori O.; Si, Rui; Tsuji‐Hosokawa, Atsumi; Cai, Hua; Yuan, Jason X.‐J.; Dillmann, Wolfgang H.

doi:10.1177/14791641231173630

Cited by 7 publications

(5 citation statements)

References 79 publications

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“…Mice with type 2 diabetes (T2D) exhibit an increase in the protein O-GlcNAcylation of cardiac endothelial cells. OGA overexpression in endothelial cells significantly reduced O-GlcNAcylation in cardiac endothelial cells, increased the CFVR and capillary density and reduced endothelial cell apoptosis in mice with T2D [72]. A study showed that rat cardiac fibroblasts cultured in high-glucose conditions had increased overall protein O-GlcNAcylation.…”

Section: Diabetic Cardiomyopathymentioning

confidence: 99%

“…Mitochondrial protein O-GlcNAcylation plays an important role in regulating cellular function; the destruction of O-GlcNAcylation homeostasis is involved in the pathogenesis of chronic diseases such as diabetes [43,72,73], neurodegenerative diseases [74,75], tumors [28,76,77] and CVDs [14,26,44]. Insulin resistance and diabetic CVDs are promoted by O-GlcNAcylation through an increase in the imbalance of multiple signaling pathways at the transcriptional, translational and posttranslational levels.…”

Section: The Regulatory Mechanisms Of Protein O-glcnacylation On Mito...mentioning

confidence: 99%

“…The rapidly increasing O-GlcNAcylation in the heart is an adaptive cardiac response that can protect cardiac function [29,132,133]. However, if the level of O-GlcNAcylation remains high in chronic disease or in the long-term (related to diabetes and overnutrition), it will lead to cardiac dysfunction [72,134,135].…”

Section: Role Of O-glcnacylation In Cardiovascular Diseases (Cvds)mentioning

confidence: 99%

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Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Qiu,

Cui,

Huang

et al. 2024

Antioxidants

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Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to the hydroxyl terminus of serine and threonine of proteins. O-GlcNAcylation is responsive to cellular stress as a reversible and posttranslational modification of nuclear, mitochondrial and cytoplasmic proteins. Mitochondrial proteins are the main targets of O-GlcNAcylation and O-GlcNAcylation is a key regulator of mitochondrial homeostasis by directly regulating the mitochondrial proteome or protein activity and function. Disruption of O-GlcNAcylation is closely related to mitochondrial dysfunction. More importantly, the O-GlcNAcylation of cardiac proteins has been proven to be protective or harmful to cardiac function. Mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance of mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs). In this review, we will focus on the interactions between protein O-GlcNAcylation and mitochondrial homeostasis and provide insights on the role of mitochondrial protein O-GlcNAcylation in CVDs.

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Section: Diabetic Cardiomyopathymentioning

confidence: 99%

Section: The Regulatory Mechanisms Of Protein O-glcnacylation On Mito...mentioning

confidence: 99%

Section: Role Of O-glcnacylation In Cardiovascular Diseases (Cvds)mentioning

confidence: 99%

See 1 more Smart Citation

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Qiu,

Cui,

Huang

et al. 2024

Antioxidants

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“…Furthermore, in diverse forms of cardiac injury, OGT hyperexpression promotes cardiac fibrosis and maladaptive remodelling, which is rescued by hyperexpression of OGA 45,149,150 . O‐GlcNAcylation stimulates collagen synthesis by cardiac fibroblasts, 151 and impairs nitric oxide synthase in endothelial cells and impairs microvascular dysfunction 152,153 . Hexokinase‐1 bound to mitochondria drives cardiac endothelial inflammation, a hallmark of heart failure and a preserved ejection fraction, and this heart failure phenotype is reportedly alleviated by inhibition of O‐GlcNAcylation 154 .…”

Section: O‐glcnacylation In the Injured Stressed And Failing Heartmentioning

confidence: 99%

“…45,149,150 O-GlcNAcylation stimulates collagen synthesis by cardiac fibroblasts, 151 and impairs nitric oxide synthase in endothelial cells and impairs microvascular dysfunction. 152,153 Hexokinase-1 bound to mitochondria drives cardiac endothelial inflammation, a hallmark of heart failure and a preserved ejection fraction, and this heart failure phenotype is reportedly alleviated by inhibition of O-GlcNAcylation. 154 Increased O-GlcNAcylation produced by OGA downregulation has deleterious effects on left ventricular function following experimental myocardial infarction 155 and contributes to right ventricular dysfunction in experimental pulmonary hypertension.…”

Section: Autophagic Fluxmentioning

confidence: 99%

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

Packer

2023

European J of Heart Fail

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The development of the foetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia‐inducible factor‐1α (HIF‐1α), which drives glycolysis. In contrast, the healthy adult heart is governed by sirtuin‐1 (SIRT1) and adenosine monophosphate‐activated protein kinase (AMPK), which promote fatty‐acid oxidation and the substantial mitochondrial ATP production required for survival in a high‐workload normoxic environment. During cardiac injury, the heart recapitulates the foetal signalling programme, which (although adaptive in the short term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct – uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) – functions as a critical nutrient surplus sensor. UDP‐GlcNAc drives the post‐translational protein modification known as O‐GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O‐GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O‐GlcNAcylation is regulated by only two enzymes, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), which adds or removes GlcNAc (N‐acetylglucosamine), respectively, from target proteins. Recapitulation of foetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O‐GlcNAcylation, both experimentally and clinically. Heightened O‐GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage‐gated sodium channels and Ca2+/calmodulin‐dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O‐GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O‐GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O‐GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signalling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP‐GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF‐1α) can promote the development of cardiomyopathy.

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eNAMPT is a novel therapeutic target for mitigation of coronary microvascular disease in type 2 diabetes

Gao,

Ramirez,

Cabrera

et al. 2024

Diabetologia

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Aims/hypothesis Individuals with diabetes are at high risk of cardiovascular complications, which significantly increase morbidity/mortality. Coronary microvascular disease (CMD) is recognised as a critical contributor to the increased cardiac mortality observed in people with diabetes. Therefore, there is an urgent need for treatments that are specific to CMD. eNAMPT (extracellular nicotinamide phosphoribosyltransferase) is a damage-associated molecular pattern and TLR4 ligand, whose plasma levels are elevated in people with diabetes. This study was thus designed to investigate the pathogenic role of intracellular nicotinamide phosphoribosyltransferase (iNAMPT) and eNAMPT in promoting the development of CMD in a preclinical murine model of type 2 diabetes. Methods An inducible type 2 diabetic mouse model was generated by a single injection of low-dose streptozocin (75 mg/kg, i.p.) combined with a high-fat diet for 16 weeks. The in vivo effects of i/eNAMPT inhibition on cardiac endothelial cell (CEC) function were evaluated by using Nampt+/− heterozygous mice, chronic administration of eNAMPT-neutralising monoclonal antibody (mAb) or use of an NAMPT enzymatic inhibitor (FK866). Results As expected, diabetic wild-type mice exhibited significantly lower coronary flow velocity reserve (CFVR), a determinant of coronary microvascular function, compared with control wild-type mice. eNAMPT plasma levels or expression in CECs were significantly greater in diabetic mice than in control mice. Furthermore, in comparison with diabetic wild-type mice, diabetic Nampt+/− heterozygous mice showed markedly improved CFVR, accompanied by increased left ventricular capillary density and augmented endothelium-dependent relaxation (EDR) in the coronary artery. NAMPT inhibition by FK866 or an eNAMPT-neutralising mAb significantly increased CFVR in diabetic mice. Furthermore, administration of the eNAMPT mAb upregulated expression of angiogenesis- and EDR-related genes in CECs from diabetic mice. Treatment with either eNAMPT or NAD+ significantly decreased CEC migration and reduced EDR in coronary arteries, partly linked to increased production of mitochondrial reactive oxygen species. Conclusions/interpretation These data indicate that increased i/eNAMPT expression contributes to the development of diabetic coronary microvascular dysfunction, and provide compelling support for eNAMPT inhibition as a novel and effective therapeutic strategy for CMD in diabetes. Graphical Abstract

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Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice

Cited by 7 publications

References 79 publications

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

Foetal recapitulation of nutrient surplus signalling by O‐GlcNAcylation and the failing heart

eNAMPT is a novel therapeutic target for mitigation of coronary microvascular disease in type 2 diabetes

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