Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus

Guzik, Tomasz J.; Mussa, Shafi; Gastaldi, Daniela; Sadowski, Jerzy; Ratnatunga, C; Pillai, Ravi; Channon, Keith M.

doi:10.1161/01.cir.0000012748.58444.08

Cited by 897 publications

(735 citation statements)

References 43 publications

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“…The effects of gp91ds‐tat to increase endothelium‐dependent vasorelaxation and to reduce eNOS glutathionylation in aorta of hyperglycemic rabbits as opposed to no effects in controls suggest that NADPH oxidase is pathologically activated in the vasculature of hyperglycemic rabbits and that its activation is upstream to glutathionylation‐mediated eNOS uncoupling and endothelial dysfunction. This is consistent with NADPH oxidase as the major source of ROS in other experimental models of diabetes34 and vessels of diabetic humans 35. Since gp91ds‐tat prevents docking of the cytosolic p47 phox subunit to the membranous gp91 phox , the isoforms activated in S961 hyperglycemia are likely Nox1 or Nox2, which require p47 phox translocation to membrane 2.…”

Section: Discussionsupporting

confidence: 81%

β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia

Galougahi

Liu

García

et al. 2016

JAHA

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BackgroundPerturbed balance between NO and O2 •−. (ie, NO/redox imbalance) is central in the pathobiology of diabetes‐induced vascular dysfunction. We examined whether stimulation of β3 adrenergic receptors (β3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re‐establish NO/redox balance, relieve oxidative inhibition of the membrane proteins eNOS and Na+‐K+ (NK) pump, and improve vascular function in a new animal model of hyperglycemia.Methods and ResultsWe established hyperglycemia in male White New Zealand rabbits by infusion of S961, a competitive high‐affinity peptide inhibitor of the insulin receptor. Hyperglycemia impaired endothelium‐dependent vasorelaxation by “uncoupling” of eNOS via glutathionylation (eNOS‐GSS) that was dependent on NADPH oxidase activity. Accordingly, NO levels were lower while O2 •− levels were higher in hyperglycemic rabbits. Infusion of the β3 AR agonist CL316243 (CL) decreased eNOS‐GSS, reduced O2 •−, restored NO levels, and improved endothelium‐dependent relaxation. CL decreased hyperglycemia‐induced NADPH oxidase activation as suggested by co‐immunoprecipitation experiments, and it increased eNOS co‐immunoprecipitation with glutaredoxin‐1, which may reflect promotion of eNOS de‐glutathionylation by CL. Moreover, CL reversed hyperglycemia‐induced glutathionylation of the β1 NK pump subunit that causes NK pump inhibition, and improved K+‐induced vasorelaxation that reflects enhancement in NK pump activity. Lastly, eNOS‐GSS was higher in vessels of diabetic patients and was reduced by CL, suggesting potential significance of the experimental findings in human diabetes.Conclusionsβ3 AR activation restored NO/redox balance and improved endothelial function in hyperglycemia. β3 AR agonists may confer protection against diabetes‐induced vascular dysfunction.

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Section: Discussionsupporting

confidence: 81%

β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia

Galougahi

Liu

García

et al. 2016

JAHA

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“…1), compared with exposure to continuous normal glucose or high glucose. The markers chosen were: (1) the basement membrane protein fibronectin, shown to be overexpressed in the vessels of diabetic patients [23]; (2) the signalling kinase PKC-β, stimulated by high glucose through a cofactor, diacylglycerol [24,25]; (3) the mitochondrial pro-apoptotic protein BCL-2 family member Bax, indicative of mitochondrial stress [26] and associated with vascular diabetic complications [27]; (4) the DNA damage protein PAR, a product of PARP, shown to be a critical factor in the development of vascular diabetic complications [7]; (5) p47phox, an inducible subunit of the enzyme NAD(P)H oxidase, shown to be a source of ROS in the endothelium of diabetic patients [28]; and (6) the protein adduct 3-NY, a marker of oxidative stress and vascular diabetic complications [29][30][31][32]. As has been shown previously, chronic high glucose resulted in significantly increased levels of: fibronectin [10]; phospho-(activated) PKC-α/βII [25]; p47phox [33]; and 3-NY [31], while the increase in Bax was not statistically significant [27] (Fig.…”

Section: Resultsmentioning

confidence: 99%

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

et al. 2007

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Aims/hypothesis A long-term 'memory' of hyperglycaemic stress, even when glycaemia is normalised, has been previously reported in endothelial cells. In this report we sought to duplicate and extend this finding. Materials and methods HUVECs and ARPE-19 retinal cells were incubated in 5 or in 30 mmol/l glucose for 3 weeks or subjected to 1 week of normal glucose after being exposed for 2 weeks to continuous high glucose. HUVECs were also treated in this last condition with several antioxidants. Similarly, four groups of rats were studied for 3 weeks: (1) normal rats; (2) diabetic rats not treated with insulin; (3) diabetic rats treated with insulin during the last week; and (4) diabetic rats treated with insulin plus α-lipoic acid in the last week. Results In human endothelial cells and ARPE-19 retinal cells in culture, as well as in the retina of diabetic rats, levels of the following markers of high glucose stress remained induced for 1 week after levels of glucose had normalised: protein kinase C-β, NAD(P)H oxidase subunit p47phox, BCL-2-associated X protein, 3-nitrotyrosine, fibronectin, poly(ADPribose) Blockade of reactive species using different approaches, i.e. the mitochondrial antioxidant α-lipoic acid, overexpression of uncoupling protein 2, oxypurinol, apocynin and the poly(ADP-ribose) polymerase inhibitor PJ34, interrupted the induction both of high glucose stress markers and of the fluorescent reactive oxygen species (ROS) probe CM-H 2 DCFDA in human endothelial cells. Similar results were obtained in the retina of diabetic rats with α-lipoic acid added to the last week of normalised glucose. Conclusions/interpretation These results provide proofof-principle of a ROS-mediated cellular persistence of vascular stress after glucose normalisation.

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“…These early observations have led other investigators to suggest that VEC are unique in their inability to modify glucose transport when exposed to extracellular high glucose concentrations, and thant an unregulated influx of high glucose levels causes overproduction of reactive oxygen species, which consequently impair VEC functions [3,4,7,8].…”

Section: Discussionmentioning

confidence: 99%

Delayed autoregulation of glucose transport in vascular endothelial cells

Alpert

Gruzman²,

Riahi³

et al. 2005

Diabetologia

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Aims/hypothesis: We aimed to characterise the development of autoregulation of glucose transport in vascular endothelial cells and its relationship to 12-lipoxygenase (12-LO) expression. Methods: Bovine aortic endothelial cells were exposed to 5.5 and 23.0 mmol/l glucose for up to 48 h. The rates of glucose transport, GLUT-1 and 12-LO expression and of 12-hydroxyeicosatetraenoic acid (12-HETE) production were determined. Results: We showed high glucose-dependent downregulation of glucose transport and transporter in vascular endothelial cells within 36-48 h. A similar time-dependent increase in the expression of 12-LO and the generation of its product 12-HETE was also observed. This downregulatory process was prevented when lipoxygenase activity was inhibited. Conclusions/interpretation: Vascular endothelial cells, which were previously thought to be "glucose-blind", do in fact downregulate GLUT-1 expression and the rate of glucose transport in response to extended exposure to high glucose concentrations. This slow development of glucose-induced downregulation in vascular endothelial cells is related to the slower basal rate of glucose transport in these cells and the slow induction of 12-LO.These data are interesting in view of current hypotheses that attribute vascular endothelial cell dysfunction in diabetes to the lack of a glucose-induced autoregulatory response.

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Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus

Cited by 897 publications

References 43 publications

β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia

β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

Delayed autoregulation of glucose transport in vascular endothelial cells

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