NO and superoxide: Opposite ends of the seesaw in cardiac contractility

Bonaventura, Joseph; Gow, Andrew J.

doi:10.1073/pnas.0405859101

Cited by 17 publications

(10 citation statements)

References 19 publications

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“…Abnormal overproduction of ROS (including superoxide anion and hydrogen peroxide) in the vasculature is involved in pathogenesis of many human disease conditions (Greenwald, 1990;Cai et al, 2003;Bonaventura and Gow, 2004). In particular, both acute (e.g., acute lung injury, hyperoxia, ischemia/reperfusion injury, inflammation, and complications of organ transplantation) and chronic (e.g., hypertension, diabetes, and atherosclerosis) vascular disorders are associated with abnormally high level of superoxide anion produced by activated leukocytes and endothelial and smooth muscle cells by pathways including NADPH-oxidase, xanthine oxidase, and mitochondrial respiratory chain (Terada et al, 1992;McCord, 2002;Christofidou-Solomidou and Muzykantov, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Superoxide anion is not a strong oxidant, but reacting with H 2 O 2 , the product of superoxide dismutation, it forms the highly reactive and damaging hydroxyl radical, whereas superoxide reaction with NO gives rise to a strong nitrating agent, peroxinitrate, and results in NO depletion, leading to the hypertensive and prothrombotic state characteristic of vascular oxidative stress (Cai et al, 2003;Bonaventura and Gow, 2004). SODs are the family of metal-containing enzymes that catalyze superoxide dismutation into H 2 O 2 and O 2 , thus alleviating these aspects of oxidative stress (McCord, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…However, an additional ROS, superoxide anion, is also involved in many types of vascular oxidative stress including ischemia/reperfusion, hypertension, stroke, infarction, and inflammation (Jia and Furchgott, 1993;Bonaventura and Gow, 2004;Loomis et al, 2005). In particular, superoxide anion, but not hydrogen peroxide, is the key culprit in vascular disorders associated with inactivation of NO by superoxide anion produced by endothelial NADPH-oxidase abnormally activated in response to angiotensin II and other proconstrictive mediators (Cai et al, 2003).…”

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confidence: 99%

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Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide

Shuvaev¹,

Tliba²,

Nakada³

et al. 2007

J Pharmacol Exp Ther

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ABSTRACT. However, another reactive oxygen species, superoxide anion, is also involved in many forms of vascular oxidative stress, including ischemia/reperfusion, hypertension, and inflammation. To protect endothelium against superoxide attack, we designed and tested antibody-directed targeting of superoxide dismutase (SOD) to the endothelial surface determinant, platelet-endothelial cell adhesion molecule (PECAM)-1. We synthesized anti-PECAM/SOD conjugates that retained 70% of enzymatic activity (superoxide anion dismutation) and specifically bound to endothelial cells, but not PECAM-negative cells. The effect of anti-PECAM/SOD delivery to cells was tested in two distinct models of oxidative stress induced by either extracellular or intracellular generation of superoxide anion. In the first model, anti-PECAM/SOD, but not unconjugated SOD, protected endothelial cells against injury caused by superoxide produced in the medium by hypoxanthine-xanthine oxidase. At the optimal dose, anti-PECAM/SOD provided up to 40 to 50% protection against cell death in this model. In the second model, anti-PECAM/SOD at the optimal dose provided complete protection against necrosis caused by paraquat-induced intracellular superoxide generation. Endothelial targeting of SOD represents a new molecular antioxidant approach that could be used for the management of vascular oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide

Shuvaev¹,

Tliba²,

Nakada³

et al. 2007

J Pharmacol Exp Ther

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“…In addition to the expansive array of crucially important biological processes in which it plays a role, NO is also a determinant of cardiac contractility. Initially NO was characterized as a contractility depressant, although the role of NO, and the NO-generating NO synthases, is now understood to be much more complex with regard to effects on cardiac contractility (90,91). Although its general biology will not be reviewed here, NO does react and interact with ROS, and this crosstalk can also have significant effects on cardiac function (92).…”

Section: Lipotoxicity and Rosmentioning

confidence: 99%

Oxygen, oxidative stress, hypoxia, and heart failure

2005

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A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.The mammalian heart is an obligate aerobic organ. At a resting pulse rate, the heart consumes approximately 8-15 ml O 2 /min/100 g tissue. This is significantly more than that consumed by the brain (approximately 3 ml O 2 /min/100 g tissue) and can increase to more than 70 ml O 2 /min/100 g myocardial tissue during vigorous exercise (1, 2). Mammalian heart muscle cannot produce enough energy under anaerobic conditions to maintain essential cellular processes; thus, a constant supply of oxygen is indispensable to sustain cardiac function and viability. The story of oxygen in the heart is complex, however, and goes well beyond its role in energy metabolism.Oxygen is a major determinant of myocardial gene expression, and as myocardial O 2 levels decrease, either during isolated hypoxia or ischemia-associated hypoxia, gene expression patterns in the heart are significantly altered (3). Oxygen participates in the generation of NO, which plays a critical role in determining vascular tone, cardiac contractility, and a variety of additional parameters. Oxygen is also central in the generation of reactive oxygen species (ROS), which can participate as benevolent molecules in cell signaling processes or can induce irreversible cellular damage and death. Oxygen is thus both vital and deleterious (4). The role of oxygen in myocardial energetics and metabolismThe heart can utilize a variety of metabolic fuels, including fatty acids, glucose, lactate, ketones, and amino acids. In the fed state, fatty acids are the preferred fuel, accounting for up to 90% of the total acetyl-CoA provided to cardiac mitochondria (5). Fatty acids are metabolized by β-oxidation, producing acetyl-CoA, NADH, and FADH 2 . The acetyl-CoA enters the Krebs cycle, producing more NADH and FADH 2 . Glucose is metabolized initially via the glycolytic pathway, producing a relatively small amount of ATP and also pyruvate, which enters the Krebs cycle, producing NADH and FADH 2 . In the absence of oxygen, the total amount of energy produced by these processes is insufficient to meet cardiac needs. The cardiac energy requirement is met, however, by entry of the resultant NADH and FADH 2 into the electron transport chain, which generates ATP by oxidative phosphorylation in the mitochondria. Oxygen serves as the terminal electron acceptor in the electron transport chain, and in the absence of sufficient oxygen, electron transport ceases and cardiac energy demands are not met (Figure 1). Generation and counterbalancing of ROSROS can be formed in the heart by a ...

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“…Superoxide anion produced by vascular cells, including endothelial cells, has also been implicated in the vascular oxidative stress in hypertension, ischemia, hyperoxia, stroke, and other conditions (Bonaventura and Gow, 2004;Loomis et al, 2005). Superoxide contributes to vascular disorders and vasoconstriction by inactivating NO and forming the strong oxidant peroxynitrite, among other mechanisms (Cai et al, 2003).…”

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confidence: 99%

Targeted Detoxification of Selected Reactive Oxygen Species in the Vascular Endothelium

Shuvaev¹,

Christofidou‐Solomidou²,

Bhora³

et al. 2009

J Pharmacol Exp Ther

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Oxidative stress underlies diverse vascular diseases, but its management remains elusive, in part because of our inability to selectively detoxify reactive oxygen species (ROS) in pathological sites and our limited understanding which species need to be eliminated. The antioxidant enzymes (AOEs) superoxide dismutase (SOD) and catalase (which decompose O 2. and H 2 O 2 , respectively), conjugated with an antibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1), bind to endothelial cells and alleviate oxidative stress in cell culture models. Here, we studied the effects of these antioxidant conjugates in mouse models of vascular oxidative stress. Anti-PECAM/catalase and anti-PECAM/SOD conjugates, in contrast to control IgG/AOE conjugates, accumulated in the lungs and vascularized organs after intravenous injection in wild-type, but not PECAM KO mice. Anti-PECAM/catalase, but not anti-PECAM/SOD, protected mice from lung injury induced by H 2 O 2 produced by glucose oxidase deposited in the pulmonary vasculature. Anti-PECAM/catalase also reduced alveolar edema and attenuated decline in arterial oxygen in mice that underwent unilateral lung ischemia/reperfusion, whereas anti-PECAM/SOD was not effective, implying the key role of H 2 O 2 in tissue damage in this pathology. In contrast, anti-PECAM/SOD, but not anti-PECAM/ catalase prevented oxidation of tetrahydrobiopterin and normalized vasoreactivity in the vessels of mice rendered hypertensive by pretreatment with angiotensin-II. This outcome agrees with reports implicating superoxide and peroxynitrite in altered endothelium-dependent vasodilatation in hypertension. Therefore, the use of endothelial cell-targeted antioxidants identifies the key specific species of ROS involved in various forms of vascular disease and holds promise for the mechanistically tailored treatment of these pathologies.Oxidative stress induced by an excess of reactive oxygen species (ROS) plays an important role in a number of vascular pathologies including hypertension, ischemia, stroke, acute myocardial infarction, and inflammation (Cai et al., 2003;Krause and Bedard, 2008). To improve management of these conditions, intense efforts are being focused on the development of ROS-detoxifying interventions. For example, nonenzymatic antioxidants, including scavengers of ROS or donors of reducing equivalents (e.g., glutathione precursors), may help alleviate subtle chronic oxidative stress, but these consumable agents provide rather marginal protection against severe oxidative stresses Porkert et al., 2008).

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NO and superoxide: Opposite ends of the seesaw in cardiac contractility

Cited by 17 publications

References 19 publications

Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide

Platelet-Endothelial Cell Adhesion Molecule-1-Directed Endothelial Targeting of Superoxide Dismutase Alleviates Oxidative Stress Caused by Either Extracellular or Intracellular Superoxide

Oxygen, oxidative stress, hypoxia, and heart failure

Targeted Detoxification of Selected Reactive Oxygen Species in the Vascular Endothelium

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