Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction

Piconi, Ludovica; Quagliaro, Lisa; Assaloni, Roberta; Ros, Roberto Da; Maier, Amabile; Zuodar, Gianni; Ceriello, Antonio

doi:10.1002/dmrr.613

Cited by 290 publications

(204 citation statements)

References 30 publications

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“…This concept is consistent with the findings that intermittent high glucose has been shown to lead to increased damage to the endothelial cells [4][5][6][7] , mesangial cells [8] and tubulointerstitial cells [9] in culture. Brownlee et al [10][11][12] have recently proposed a "unifying mechanism" by which all the pathways involved in the pathogenesis of diabetic complications are linked through a hyperglycemia-driven intracellular excess of reactive oxygen species (ROS), superoxide anion in particular.…”

Section: Introductionsupporting

confidence: 91%

Attenuated Superoxide Dismutase Induction in Retinal Cells in Response to Intermittent High Versus Continuous High Glucose

Ihnat¹,

Kaltreider²,

Thorpe³

et al. 2007

American J. of Biochemistry and Biotechnology

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High glucose, particularly in oscillating conditions, produces an increase in oxidative stress and has been shown to result in an increase in diabetic complications, retinopathy in particular. The hypothesis of this work was that chronic exposure to intermittent high glucose results in an attenuated induction of an antioxidant response as compared to continuous high glucose exposure in isolated retinal cells In this work, human retinal pericytes and ARPE-19 cells were exposed to 5 mM or 30 mM continuous high glucose or to 5 mM oscillating daily with 30 mM glucose for 14 days. Levels of antioxidant proteins and activity and levels of reactive species protein adducts were measured. We demonstrate that the induction of total cellular superoxide dismutase (SOD) activity in isolated retinal pericytes and ARPE-19 cells is significantly attenuated in response to oscillating glucose as compared to continuous high glucose. We also show that a marker of nitrosative stress, 3-nitrotyrosine and a general marker of oxidized proteins, OxyBlot™, were significantly increased in both cell types exposed to intermittent high glucose as compared to continuous high glucose. Finally, we show that levels of nitrated MnSOD were increased in response to intermittent high versus continuous high glucose and that the addition of a reactive nitrogen species scavenger to oscillating glucose resulted in significantly increased levels of SOD activity. In conclusion, our results demonstrate for the first time a link between intermittent high glucose and a decreased induction of an antioxidant response of SOD.

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Section: Introductionsupporting

confidence: 91%

Attenuated Superoxide Dismutase Induction in Retinal Cells in Response to Intermittent High Versus Continuous High Glucose

Ihnat¹,

Kaltreider²,

Thorpe³

et al. 2007

American J. of Biochemistry and Biotechnology

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“…T2DM is also characterized by the presence of oxidative stress (Davi et al 1999), and diabetic patients with NAFLD have higher levels of markers of oxidative stress compared to diabetic patients without NAFLD (Narasimhan et al 2010). Recently, several studies have demonstrated that IHG can generate more ROS than SHG in endothelial cells (Quagliaro et al 2003, Piconi et al 2006, islet cell (Del Guerra et al 2007, Kim et al 2012 and Schwann cells (Sun et al 2012a,b). We found that in the presence of lipotoxicity, SHG produced an increase in oxidative stress; moreover, the IHG appeared to further enhance oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Yin¹,

Zheng²,

Pan³

et al. 2015

Journal of Molecular Endocrinology

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Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 mmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.

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“…In diabetic rats, pharmacological inhibition of PARP not only prevents, but also reverses endothelial dysfunction [12]. There are in vitro findings showing that oscillations in blood glucose concentration, themselves, can provoke increased free radical formation and consequent PARP activation, culminating in pathological changes in the vascular endothelium, leading to endothelial dysfunction [19,35,36]. Our in vivo findings are consistent with in vitro studies in cultured human umbilical vein endothelial cells, in demonstrating that rapid glycaemic swings result in the most substantial increase in vascular PARP activation.…”

Section: Discussionmentioning

confidence: 99%

Rapid ‘glycaemic swings’ induce nitrosative stress, activate poly(ADP-ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus

et al. 2009

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Aim/hypothesis Postpandrial hyperglycaemia is a significant risk factor for the development of macrovascular diseases. There is no clear agreement in the field whether these alterations result from hyperglycaemic episodes or from exaggerated alterations ('glycaemic swings') in blood glucose. We compared the effect of stable high glucose with a model of poorly maintained insulin-controlled diabetes (on average lower glucose, but with large glycaemic swings) on the development of endothelial dysfunction in rats. Methods Intermediate-or long-acting insulin was used to reduce mean blood glucose levels. One group of animals had stable low glucose levels, while animals in the other group exhibited rapid changes ('swings') in their blood glucose concentration. Acetylcholine-induced endothelium-dependent vascular relaxation of the thoracic aorta was measured. Immunohistochemistry, western blot analysis and flow cytometry were used to determine nitrotyrosine formation and poly(ADP-ribose) accumulation in the aorta, in circulating leucocytes and in bone marrow cells. Results Steady normalisation of blood glucose levels (a model of well-controlled diabetes) protected against the development of endothelial dysfunction, poly(ADP-ribose) polymerase (PARP) activation and nitrotyrosine production. However, impairment of endothelium-dependent relaxation was found in the animals undergoing glycaemic swings, even though the fructosamine levels in these animals were lower than in the untreated diabetic rats. This was associated with elevated PARP activation in the aorta and in bone marrow cells that was similar to or even more pronounced than that seen in the untreated diabetic animals. Conclusions/interpretation Large glycaemic swings exert deleterious cardiovascular effects in diabetes mellitus, in part via enhanced activation of the PARP pathway.

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Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction

Cited by 290 publications

References 30 publications

Attenuated Superoxide Dismutase Induction in Retinal Cells in Response to Intermittent High Versus Continuous High Glucose

Attenuated Superoxide Dismutase Induction in Retinal Cells in Response to Intermittent High Versus Continuous High Glucose

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Rapid ‘glycaemic swings’ induce nitrosative stress, activate poly(ADP-ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus

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