Adenovirus-Mediated Overexpression of
            <i>O</i>
            -GlcNAcase Improves Contractile Function in the Diabetic Heart

Hu, Ying; Belke, Darrell D.; Suárez, Jorge; Swanson, Eric A.; Clark, Roger; Hoshijima, Masahiko; Dillmann, Wolfgang H.

doi:10.1161/01.res.0000165478.06813.58

Cited by 205 publications

(197 citation statements)

References 59 publications

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“…Several groups have shown that prolonged elevation of O-GlcNAc levels attenuates insulin signaling [17,22], though this issue is far from reconciled [42]. Hu et al showed that altered O-GlcNAcylation in diabetic hearts contributes to cardiac dysfunction and calcium handling [43]. Such efforts support the emerging notion that O-GlcNAc signaling participates in the pathogenesis of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Non-canonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition

Ngoh

Watson

Facundo

et al. 2008

Journal of Molecular and Cellular Cardiology

113

151

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O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic, inducible, and reversible posttranslational modification of nuclear and cytoplasmic proteins on Ser/ Thr amino acid residues. In addition to its putative role as a nutrient sensor, we have recently shown pharmacologic elevation of O-GlcNAc levels positively affected myocyte survival during oxidant stress. However, no rigorous assessment of the contribution of O-GlcNAc transferase has been performed, particularly in the posthypoxic setting. Therefore, we hypothesized that pharmacological or genetic manipulation of OGlcNAc transferase (OGT), the enzyme that adds O-GlcNAc to proteins, would affect cardiac myocyte survival following hypoxia/reoxygenation (H/R). Adenoviral overexpression of OGT (AdOGT) in cardiac myocytes augmented O-GlcNAc levels and reduced post-hypoxic damage. Conversely, pharmacologic inhibition of OGT significantly attenuated O-GlcNAc levels, exacerbated post-hypoxic cardiac myocyte death, and sensitized myocytes to mitochondrial membrane potential collapse. Both genetic deletion of OGT using a cre-lox approach and translational silencing via RNAi also resulted in significant reductions in OGT protein and O-GlcNAc levels, and, exacerbated post-hypoxic cardiac myocyte death. Inhibition of OGT reduced O-GlcNAc levels on voltage dependent anion channel (VDAC) in isolated mitochondria and sensitized to calcium-induced mitochondrial permeability transition pore (mPTP) formation, indicating mPTP may be an important target of O-GlcNAc signaling and confirming the aforementioned mitochondrial membrane potential results. These data demonstrate that OGT exerts pro-survival actions during hypoxia-reoxygenation in cardiac myocytes, particularly at the level of mitochondria.

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Section: Discussionmentioning

confidence: 99%

Non-canonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition

Ngoh

Watson

Facundo

et al. 2008

Journal of Molecular and Cellular Cardiology

113

151

View full text Add to dashboard Cite

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“…Mice were made hyperglycaemic by a single injection of freshly prepared STZ solution (200 mg/kg body weight in citrate saline, pH 4.2, i.p. ; Alexis, Lausanne, Switzerland) [26]. The mice were housed in cages of four mice each and had unlimited access to water and standard mouse chow.…”

Section: Methodsmentioning

confidence: 99%

Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes

et al. 2008

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Aims/hypothesis Diabetic patients are at increased risk of cardiomyopathy, acute myocardial infarction and loss of cardiac progenitor cells (CPCs), but the aetiology is poorly understood. We hypothesised a significant role for mannose-binding lectin (MBL) in cardiomyopathies associated with hyperglycaemia. Methods The role of MBL in myocardial ischaemia and reperfusion (MI/R) injury was investigated in wild-type (WT) and MBL-null mice following 2 weeks of streptozotocin-induced hyperglycaemia. Results Hyperglycaemic WT mice presented with significantly decreased left ventricular ejection fractions and increased serum troponin I levels and myocardial inflammation compared with non-diabetic WT mice following MI/R. Hyperglycaemic MBL-null mice or insulin-treated diabetic WT mice were significantly protected from MI/R injury compared with diabetic WT mice. In an additional study using diabetic WT mice, echocardiographic measurements demonstrated signs of dilative cardiomyopathy, whereas heart:body weight ratios suggested hypertrophic cardiac remodelling after 2 weeks of hyperglycaemia. Immunohistochemical analysis of CPCs showed significantly lower numbers in diabetic WT hearts compared with non-diabetic hearts. Insulin-treated diabetic WT or untreated diabetic MBL-null mice were protected from dilative cardiomyopathy, hypertrophic remodelling and loss of CPCs. Conclusions/interpretationThese data demonstrate that MBL may play a critical role in diabetic MI/R injury. Further, the absence of MBL appears to inhibit hypertrophic remodelling and hyperglycaemia-induced loss of CPCs after just 2 weeks of hyperglycaemia in mice.

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“…Finally, elevating levels of glucose in neonatal cardiomyocytes resulted in augmented O-GlcNAc levels and subsequently reduced function of mitochondrial electron transport complexes I, III, and IV (Hu et al 2005), however, its role in stress has not been studied yet. Interestingly, overexpressing O-GlcNAcase to reduce O-GlcNAc levels can reverse the effects of reduced mitochondrial function when glucose levels are elevated (Hu et al 2005). …”

Section: Mitochondrial Dynamicsmentioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

120

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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Adenovirus-Mediated Overexpression of O -GlcNAcase Improves Contractile Function in the Diabetic Heart

Cited by 205 publications

References 59 publications

Non-canonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition

Non-canonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition

Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

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