Peroxynitrite Disrupts Endothelial Caveolae Leading to eNOS Uncoupling and Diminished Flow-Mediated Dilation in Coronary Arterioles of Diabetic Patients

Cassuto, James; Dou, Huijuan; Czikora, István; Szabó, András; Patel, Vijay; Kamath, Vinayak; Chantemèle, Eric J. Belin de; Fehér, Attila; Romero, Maritza J.; Bagi, Zsolt

doi:10.2337/db13-0577

Cited by 108 publications

(91 citation statements)

References 48 publications

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“…It is of great interest that NO availability can be compromised by interactions with superoxide anion, with a by-product of this reaction being the generation of peroxynitrite (OONO 2 ), an ROS that itself is known to mediate deleterious effects on the cardiovascular system in diabetes (10). However, prior to the study of Cassuto et al (11), which appears in this issue, the specific impact of OONO 2 on the endothelial caveolae, which is required for the proper functionality of endothelial NO synthase (eNOS) (12), and the subsequent effect of this interaction on NO-regulated FMD in response to changes in wall shear stress in conditions of human diabetes had not been rigorously addressed in the scientific literature.…”

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confidence: 93%

“…The findings of Cassuto et al (11) provide important new information regarding the underlying cellular mechanisms responsible for vasomotor dysfunctions in coronary arterioles in diabetic humans. These results could be used as the basis for the design of interventions to improve coronary blood flow and cardiac function in diabetes by the prevention of free radical overproduction and sequestration of free radicals, although this topic remains controversial (3,12).…”

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confidence: 99%

“…Cassuto et al (11) have provided a comprehensive in vitro evaluation of the relationships among OONO 2 levels, caveolae assembly in endothelial membranes, eNOS functionality, and FMD in coronary arterioles from diabetic human subjects, using sound and reliable pharmacologic and genetic approaches. Therefore, there is clear clinical relevance of the findings to increasing our understanding of the etiology of coronary microcirculatory disease in human diabetes.…”

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A Radical Concept on Caveolae and Endothelial Dysfunction in Coronary Microvascular Disease in Diabetes

Henriksen

2014

Diabetes

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The risk of cardiovascular disease is markedly elevated in individuals with diabetes, representing the primary cause of morbidity and mortality in these diabetic patients (1). More specifically, individuals with diabetes display dysfunctions in the regulation of blood flow in coronary arterioles (2,3). Importantly, impairments in the appropriate vasodilatory response of myocardial arterioles to various pharmaceutical and physical stimuli can be present even if there is no discernible atherosclerotic blockage in these blood vessels (4,5). Moreover, increased flow-mediated dilation (FMD) in coronary arterioles is an important regulatory mechanism for controlling arteriolar diameter and blood flow in response to changes in wall shear stress, and this mechanism is also impaired in conditions of glucose dysregulation (6,7).While the underlying etiology for the dysfunctions in the coronary microcirculation in diabetes is certainly multifactorial, the contribution of impairments in the endothelial nitric oxide (NO)-generating system and their association with the excess generation of reactive oxygen species (ROS) appears to be crucial in the development of these vascular abnormalities. For example, the impairment of the induction of vasodilation in coronary arterioles in the db/db mouse, a model of obesity-associated insulin resistance and type 2 diabetes, is related to limitations in NO availability (8,9). It is of great interest that NO availability can be compromised by interactions with superoxide anion, with a by-product of this reaction being the generation of peroxynitrite (OONO 2 ), an ROS that itself is known to mediate deleterious effects on the cardiovascular system in diabetes (10). However, prior to the study of Cassuto et al. (11), which appears in this issue, the specific impact of OONO 2 on the endothelial caveolae, which is required for the proper functionality of endothelial NO synthase (eNOS) (12), and the subsequent effect of this interaction on NO-regulated FMD in response to changes in wall shear stress in conditions of human diabetes had not been rigorously addressed in the scientific literature.The study of Cassuto et al. (11) convincingly advances the concept that, in human diabetes, defects in the ability of NO to facilitate vasodilation in coronary arterioles under conditions of increased OONO 2 exposure are related to the impaired expression of the caveloin-1 (Cav-1), an important structural component of caveolae in the endothelial membrane. Using tissue isolated from older nondiabetic subjects and subjects with either type 1 or 2 diabetes, the authors demonstrated that in vitro increases in FMD due to enhanced wall shear stress were severely reduced in coronary arterioles from diabetic subjects compared with coronary arterioles from nondiabetic subjects. Moreover, these vasomotor defects were associated with augmented OONO 2 production, as reflected by 3-nitrotyrosine levels (a biomarker of OONO 2 -mediated protein nitration), and were reproduced by direct incubation of arterioles with OONO...

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A Radical Concept on Caveolae and Endothelial Dysfunction in Coronary Microvascular Disease in Diabetes

Henriksen

2014

Diabetes

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“…16) Nitric oxide (NO) is synthesized by three nitric oxide synthases. 17,18) The NOsuperoxide interaction not only decreases the bioavailability of NO, but also produces the reactive peroxynitrate (a ROS), 19) which disrupts endothelial membrane caveolae, cholesterolrich membrane lipid rafts.…”

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confidence: 99%

High Expression Levels of NADPH Oxidase 3 in the Cerebrum of Ten-Week-Old Stroke-Prone Spontaneously Hypertensive Rats

Michihara

Oda

Mido

2016

Biological & Pharmaceutical Bulletin

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We previously demonstrated that the high levels of oxidative stress in the brains of ten-week-old strokeprone hypertensive rats (SHRSP) were attributable to intrinsic, not extrinsic factors (Biol. Pharm. Bull., 33, 2010, Michihara et al.). The aim of the present study was to determine whether increases in the enzymes producing reactive oxygen species (ROS), reductions in the enzymes and proteins removing ROS, or increases in an enzyme and transporter removing antioxidants promoted oxidative stress in the SHRSP cerebrum. No significant decreases were observed in the mRNA levels of enzymes that remove ROS between SHRSP and normotensive Wistar Kyoto rats. The activity of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and the protein and mRNA levels of NOX3, an enzyme that produces ROS, were significantly increased in the SHRSP cerebrum. These results suggested that the high expression levels of NOX3 increased oxidative stress in the SHRSP cerebrum.Key words oxidative stress; brain; oxidase; stroke; rat Reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and the hydroxyl radical, are byproducts of oxygen metabolism in cells, and are produced in all oxygenutilizing organs. Oxidative stress is known to occur when an imbalance exists between the production and removal of ROS by the antioxidant system. 1) Oxidative stress has been implicated in the development of several diseases such as cancer, Alzheimer's disease, cardiovascular disease, hypertension, and stroke.2,3) The main cause of stroke is hypertension. An epidemiological study identified lower serum cholesterol levels as a cause of cerebral hemorrhage.4) On the other hand, ROS have been shown to play a role in the development of brain injury following cerebral hemorrhage, 5) and secondary brain injury after cerebral hemorrhage has also been associated with oxidative stress. 6) These findings suggest that not only hypertension and lower serum cholesterol levels, but also oxidative stress is responsible for the development of stroke.Oxidative stress is generally caused by an increase in the levels of enzymes producing ROS and free radicals, or a reduction in antioxidant levels or the enzymes that remove ROS and free radicals. Superoxide dismutase (SOD) catalyzes the conversion of superoxide to hydrogen peroxide (H 2 O 2 ), which is then reduced to H 2 O and O 2 by catalase (CAT), the glutathione system, comprising glutathione peroxidase (GPX) and glutathione reductase (GR), 7) or the thioredoxin system, which consists of thioredoxin (TXN), peroxiredoxin (PRX), and thioredoxin reductase (TXNR).8) A previous study reported that the main enzymes detoxifying H 2 O 2 were the glutathione system in the brain, the TXN system in mitochondria, and catalase in peroxisomes. 9) Uncoupling protein 2 (UCP2), which is a mitochondrial inner membrane carrier protein, acts as a negative regulator of ROS production. 10) Uric acid, which is a natural antioxidant, was previously reported to be effluxed by ATP-binding cassette subfamily G ...

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“…Diabetic complications are associated with oxidative stress and uncoupling of endothelial nitric oxide synthase (eNOS, type 3) (reviewed in [3]). Both parameters are considered important pathological mechanisms in the development of vascular dysfunction in diabetic animals [4][5][6] and patients [7,8]. Another major cause for vascular damage under hyperglycemic conditions is based on direct toxic effects of high glucose levels via the formation of advanced glycation end products (AGE) and activation of their specific receptors (RAGE) [9,10].…”

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confidence: 99%

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

Hanf

Steven

Oelze

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance ® ), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF-Lepr fa/fa and 16 ZDF-Lepr +/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).

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Peroxynitrite Disrupts Endothelial Caveolae Leading to eNOS Uncoupling and Diminished Flow-Mediated Dilation in Coronary Arterioles of Diabetic Patients

Cited by 108 publications

References 48 publications

A Radical Concept on Caveolae and Endothelial Dysfunction in Coronary Microvascular Disease in Diabetes

A Radical Concept on Caveolae and Endothelial Dysfunction in Coronary Microvascular Disease in Diabetes

High Expression Levels of NADPH Oxidase 3 in the Cerebrum of Ten-Week-Old Stroke-Prone Spontaneously Hypertensive Rats

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

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