Methylglyoxal promotes oxidative stress and endothelial dysfunction

Sena, Cristina M.; Matafome, Paulo; Crisóstomo, Joana; Rodrigues, Lisa; Fernandes, Rosa; Pereira, Paulo; Seiça, Raquel

doi:10.1016/j.phrs.2012.03.004

Cited by 181 publications

(118 citation statements)

References 55 publications

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“…Studies have also shown an increased expression of RAGE in cerebral microvessels in animal models of AD, a result that we have managed to replicate [26,27]. An increase in the expression of RAGE has been observed in a model of formation of AGEs in vivo induced by methylglyoxal, a reactive aldehyde formed in glucose oxidation or lipid peroxidation [28]. The same study also showed that an increase formation of AGEs is capable of causing endothelial dysfunction, and as such the AGE-RAGE system is a possible cause for the vascular abnormalities observed in our study.…”

Section: Discussionmentioning

confidence: 71%

β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

Herculano

Tamura

Ohba

et al. 2013

JAD

110

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Abstract. Our goal in this study was to determine whether or not feeding young (4 months old) Alzheimer's disease model transgenic mice with a high fat diet (HFD), consisting of 32% fat, is capable of causing cognitive decline and whether treatment with ␤-alanyl-L-histidine (carnosine) is capable of reducing these effects. Carnosine is an endogenous antioxidant and antiglycating agent that is abundantly present in the brain and muscle tissues of vertebrates. After 8 weeks of feeding with HFD, we observed a significant decline in the contextual memory in transgenic mice fed with HFD as compared to transgenic mice fed with a normal diet as well as to normal diet-wild type mice. Treatment with carnosine at a dose of 5 mg/day for 6 weeks was effective in preventing cognitive decline, as the transgenic group fed with HFD and treated with carnosine displayed a level of cognition comparable to controls. No differences in senile plaque load were observed between all groups. However, we observed an increase in the expression of RAGE in blood vessels as well as increased microglial activation in the hippocampus of animals fed with HFD, effects that were reversed when treated with carnosine. Given these results, there is a possibility that inflammation and cerebrovascular abnormalities might be the cause of cognitive decline in this model.

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Section: Discussionmentioning

confidence: 71%

β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

Herculano

Tamura

Ohba

et al. 2013

JAD

110

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“…This AGE compound is a major contributor of hyperglycemia-induced oxidative stress. 38,39 A recent study has shown that p66…”

Section: Indeed Selective Inhibition Of Pkc␤ii Interrupted Mitochondmentioning

confidence: 99%

Gene Silencing of the Mitochondrial Adaptor p66 ^Shc Suppresses Vascular Hyperglycemic Memory in Diabetes

Paneni

Mocharla

Akhmedov

et al. 2012

Circulation Research

223

201

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Rationale: Hyperglycemic memory may explain why intensive glucose control has failed to improve cardiovascular outcomes in patients with diabetes. Indeed, hyperglycemia promotes vascular dysfunction even after glucose normalization. However, the molecular mechanisms of this phenomenon remain to be elucidated.Objective: The present study investigated the role of mitochondrial adaptor p66 Shc in this setting. Methods and Results:In human aortic endothelial cells (HAECs) exposed to high glucose and aortas of diabetic mice, activation of p66Shc by protein kinase C ␤II (PKC␤II) persisted after returning to normoglycemia. Persistent p66Shc upregulation and mitochondrial translocation were associated with continued reactive oxygen species (ROS) production, reduced nitric oxide bioavailability, and apoptosis. We show that p66Shc gene overexpression was epigenetically regulated by promoter CpG hypomethylation and general control nonderepressible 5-induced histone 3 acetylation. Furthermore, p66Shc -derived ROS production maintained PKC␤II upregulation and PKC␤II-dependent inhibitory phosphorylation of endothelial nitric oxide synthase at Thr-495, leading to a detrimental vicious cycle despite restoration of normoglycemia. Moreover, p66Shc activation accounted for the persistent elevation of the advanced glycated end product precursor methylglyoxal. In vitro and in vivo gene silencing of p66Shc , performed at the time of glucose normalization, blunted ROS production, restored endothelium-dependent vasorelaxation, and attenuated apoptosis by limiting cytochrome c release, caspase 3 activity, and cleavage of poly (ADP-ribose) polymerase. Conclusions: p66Shc is the key effector driving vascular hyperglycemic memory in diabetes. Our study provides molecular insights for the progression of diabetic vascular complications despite glycemic control and may help to define novel therapeutic targets. (Circ Res. 2012;111:278-289.) Key Words: vascular disease Ⅲ diabetes mellitus Ⅲ free radicals Ⅲ endothelium T he prevalence of diabetes has dramatically increased worldwide, with a further rise anticipated in the next decades. 1,2 Morbidity and mortality from cardiovascular disease is 2-to 8-fold higher in subjects with than in those without diabetes. 3 Editorial, see p 262Recent prospective clinical trials have failed to confirm unequivocal benefits from normalization of glycemia on cardiovascular outcomes. 4 -8 In these trials, intensive glucoselowering therapy was started after a median duration of diabetes ranging from 8 to 11 years. 4 -8 By contrast, early treatment of hyperglycemia reduces the risk of myocardial infarction, diabetes-related deaths, and all-cause mortality. 9 -11 These observations support the concept that hyperglycemic environment may be remembered in the vasculature. 12 Reactive oxygen species (ROS) are probably involved in this phenomenon defined "hyperglycemic memory," but the underlying molecular mechanisms remain unknown. [13][14][15] Overproduction of ROS by mitochondria is considered as a causal link betwe...

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“…AGEs are thought to impair endothelium-dependent vasodilatation in diabetes (Gao et al, 2008;Sena et al, 2012). Our previous study found that AGEs impaired IK Ca -and SK Ca -mediated relaxation in rat mesenteric arteries via downregulation of K Ca 3.1 and K Ca 2.3 channels induced by oxidative stress (Zhao et al, 2014).…”

Section: Introductionmentioning

confidence: 98%

Metformin Restores Intermediate-Conductance Calcium-Activated K⁺Channel– and Small-Conductance Calcium-Activated K⁺Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

et al. 2014

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The present study was designed to investigate the effect of metformin on the impairment of intermediate-conductance and small-conductance Ca 21-activated potassium channels (IK Ca and SK Ca )-mediated relaxation in diabetes and the underlying mechanism. The endothelial vasodilatation function of mesenteric arteries was assessed with the use of wire myography. Expression levels of IK Ca and SK Ca and phosphorylated Thr 172 of AMPactivated protein kinase (AMPK) were measured using Western blot technology. The channel activity was observed using a whole-cell patch voltage clamp. Reactive oxygen species (ROS) were measured using dihydroethidium and 29,79-dichlorofluorescein diacetate. Metformin restored the impairment of IK Ca -and SK Camediated vasodilatation in mesenteric arteries from streptozotocininduced type 2 diabetic rats and that from normal rats incubated with advanced glycation end products (AGEs) for 3 hours. In cultured human umbilical vein endothelial cells (HUVECs), 1 mM metformin reversed AGE-induced increase of ROS and attenuated AGEand H 2 O 2 -induced downregulation of IK Ca and SK Ca after longterm incubation (.24 hours). Short-term treatment (3 hours) with 1 mM metformin reversed the decrease of IK Ca and SK Ca currents induced by AGE incubation for 3 hours without changing the channel expression or the AMPK activation in HUVECs. These results are the first to demonstrate that metformin restored IK Ca -and SK Ca -mediated vasodilatation impaired by AGEs in rat mesenteric artery, in which the upregulation of channel activity and protein expression is likely involved.

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Methylglyoxal promotes oxidative stress and endothelial dysfunction

Cited by 181 publications

References 55 publications

β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

Gene Silencing of the Mitochondrial Adaptor p66 ^Shc Suppresses Vascular Hyperglycemic Memory in Diabetes

Metformin Restores Intermediate-Conductance Calcium-Activated K⁺Channel– and Small-Conductance Calcium-Activated K⁺Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

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Methylglyoxal promotes oxidative stress and endothelial dysfunction

Cited by 181 publications

References 55 publications

β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

Gene Silencing of the Mitochondrial Adaptor p66 Shc Suppresses Vascular Hyperglycemic Memory in Diabetes

Metformin Restores Intermediate-Conductance Calcium-Activated K+Channel– and Small-Conductance Calcium-Activated K+Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

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Gene Silencing of the Mitochondrial Adaptor p66 ^Shc Suppresses Vascular Hyperglycemic Memory in Diabetes

Metformin Restores Intermediate-Conductance Calcium-Activated K⁺Channel– and Small-Conductance Calcium-Activated K⁺Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery