Endothelial Cells Negatively Modulate Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells

Xu, Shaoping; He, Ying; Vokurková, M.; Touyz, Rhian M.

doi:10.1161/hypertensionaha.109.133983

Cited by 37 publications

(21 citation statements)

References 48 publications

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“…ROS production is increased in VSMCs from resistance arteries of hypertensive patients, and this is associated with up-regulation of vascular Nox (75,112,142,207,213,233). The importance of Nox in human cardiovascular disease is supported by studies showing that polymorphisms in Nox subunits are associated with increased atherosclerosis and hypertension.…”

Section: Ros Oxidative Stress and Human Hypertensionmentioning

confidence: 99%

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Montezano

Touyz²

2014

Antioxidants & Redox Signaling

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229

177

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Significance: Reactive oxygen species (ROS) are signaling molecules that are important in physiological processes, including host defense, aging, and cellular homeostasis. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in the onset and/or progression of chronic diseases, including hypertension. Recent Advances: Although oxidative stress may not be the only cause of hypertension, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors, such as salt loading, activation of the renin-angiotensin-aldosterone system, and sympathetic hyperactivity, at least in experimental models. A major source for ROS in the cardiovascular-renal system is a family of nicotinamide adenine dinucleotide phosphate oxidases (Noxs), including the prototypic Nox2-based Nox, and Nox family members: Nox1, Nox4, and Nox5. Critical Issues: Although extensive experimental data support a role for increased ROS levels and altered redox signaling in the pathogenesis of hypertension, the role in clinical hypertension is unclear, as a direct causative role of ROS in blood pressure elevation has yet to be demonstrated in humans. Nevertheless, what is becoming increasingly evident is that abnormal ROS regulation and aberrant signaling through redoxsensitive pathways are important in the pathophysiological processes which is associated with vascular injury and target-organ damage in hypertension. Future Directions: There is a paucity of clinical information related to the mechanisms of oxidative stress and blood pressure elevation, and a few assays accurately measure ROS directly in patients. Such further ROS research is needed in humans and in the development of adequately validated analytical methods to accurately assess oxidative stress in the clinic. Antioxid. Redox Signal. 20,[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182]

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Section: Ros Oxidative Stress and Human Hypertensionmentioning

confidence: 99%

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Montezano

Touyz²

2014

Antioxidants & Redox Signaling

Self Cite

229

177

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“…80 It has been reported that Oxidative stress in hypertension R Rodrigo et al impaired thioredoxin expression in spontaneously hypertensive rats 81 and in endothelial cells negatively regulates ROS production in VSMC through thioredoxin upregulation. 82 Thus, thioredoxin could be an important therapeutic target for the prevention and treatment of oxidative stress and hypertension. [83][84][85] Recent studies have shown that the antioxidant effects of mildly elevated serum bilirubin levels may protect against diseases that are associated with oxidative stress 86 through mechanisms that decrease oxidative stress and increase NO levels.…”

Section: Endogenous Antioxidantsmentioning

confidence: 99%

The role of oxidative stress in the pathophysiology of hypertension

2011

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Hypertension is considered to be the most important risk factor in the development of cardiovascular disease. An increasing body of evidence suggests that oxidative stress, which results in an excessive generation of reactive oxygen species (ROS), has a key role in the pathogenesis of hypertension. The modulation of the vasomotor system involves ROS as mediators of vasoconstriction induced by angiotensin II, endothelin-1 and urotensin-II, among others. The bioavailability of nitric oxide (NO), which is a major vasodilator, is highly dependent on the redox status. Under physiological conditions, low concentrations of intracellular ROS have an important role in the normal redox signaling maintaining vascular function and integrity. However, under pathophysiological conditions, increased levels of ROS contribute to vascular dysfunction and remodeling through oxidative damage. In human hypertension, an increase in the production of superoxide anions and hydrogen peroxide, a decrease in NO synthesis and a reduction in antioxidant bioavailability have been observed. In turn, antioxidants are reducing agents that can neutralize these oxidative and otherwise damaging biomolecules. The use of antioxidant vitamins, such as vitamins C and E, has gained considerable interest as protecting agents against vascular endothelial damage. Available data support the role of these vitamins as effective antioxidants that can counteract ROS effects. This review discusses the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of vascular damage in hypertension, and the possible therapeutic strategies that could prevent or treat this disorder. Hypertension Research (2011) 34, 431-440; doi:10.1038/hr.2010.264; published online 13 January 2011Keywords: antioxidants; endothelial dysfunction; oxidative stress INTRODUCTION Hypertension is considered the most important risk factor for the occurrence of cardiovascular disease. 1 Oxidative stress has gained attention as one of the fundamental mechanisms responsible for the development of hypertension. Reactive oxygen species (ROS) have an important role in the homeostasis of the vascular wall; hence, they could be part of the mechanism that leads to hypertension. 2-4 Thus, increased ROS production, reduced nitric oxide (NO) levels and reduced antioxidant bioavailability were demonstrated in experimental and human hypertension. Vascular superoxide is primarily derived from nicotinamide adenine dineucleotide phosphate (NADPH) oxidase when stimulated by hormones, such as angiotensin II (AT-II), endothelin-1 (ET-1) and urotensin II. In addition, increased ROS production may be generated by mechanical stimuli on the vascular wall, which increase with hypertension. ROS-induced vasoconstriction results from increased intracellular calcium concentration, thereby contributing to the pathogenesis of hypertension. 2 Vasomotor tone is dependent on a delicate balance between vasoconstrictor and vasodilator forces that result from the interaction between the components of...

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“…A complex mixture of endothelial autocoids involving NO, cyclooxygenase 2 products, hydroxyeicosatetraenoic acids, and NADPH oxidase-derived ROS appears to contribute to this effect. 49 Collectively, these observations suggest that a substantial part of the vascular but also cardiac effects of angiotensin II is a consequence of indirect actions involving the MRdependent induction and activation of NADPH oxidases. Similar observations, although largely based on pharmacological data, have been made for serotonin and the adrenoceptors: inhibition of the 5-HT(2B) receptor for serotonin reduced the ROS production and cardiac hypertrophy in response to angiotensin II.…”

Section: Brandes Vascular Functions Of Nadph Oxidasesmentioning

confidence: 98%

Vascular Functions of NADPH Oxidases

Brandes

2010

Hypertension

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NADPH oxidases belong to a group of enzymes that generate reactive oxygen species (ROS) by electron transfer from NADPH to molecular oxygen. The product of this reaction is the superoxide anion (O 2 Ϫ ), which undergoes secondary reactions. O 2 Ϫ inactivates NO to yield peroxynitrite and spontaneously or under catalysis of superoxide dismutases reacts to hydrogen peroxide. NADPH oxidases, therefore, limit vascular NO availability and facilitate reactions involving ROS. 1 It is now well understood that endothelial dysfunction is largely a consequence of NADPH oxidase activation, as well as of complex secondary reactions that involve different types of ROS. Peroxynitrite oxidizes the NO synthase cofactor tetrahydrobiopterin and stimulates kinases, which both lead to uncoupling of the endothelial NO synthase. NO and O 2 Ϫ may also affect gene expression, and, in particular, NADPH oxidase-derived hydrogen peroxide has been shown to be important in this respect. In addition to the stress-mediated ROS-stimulated gene expression, hydrogen peroxide transiently or irreversibly oxidizes biological materials and, therefore, has complex effects on signaling that are still incompletely elucidated. 1 NADPH Oxidases From Past to PresentAlthough the initial work on NADPH oxidases focused on its role for gene expression and endothelial dysfunction at large, the research of recent years aimed at the identification of specific NADPH oxidase-dependent signaling pathways, the understanding of the role of the enzymes in individual disease entities, the identification of NADPH oxidase inhibitors, and finally the demonstration of a relevance of NADPH oxidases in human cardiovascular diseases. Indeed, it is now known that patients with chronic granulomatous disease, which results from loss-of-function mutations of the NADPH oxidase, have an increased vascular NO availability and reduced vascular levels of footprint markers of ROS formation. 2 This important observation provided a direct link between NADPH oxidase and endothelial function in humans. Chronic granulomatous disease, however, is too rare and too severe to study whether the advantage in endothelial function also translates into a reduced cardiovascular disease rate. Studies on polymorphisms of NADPH oxidase genes, however, failed to draw a clear picture. 3 Thus, most data in support of a relevance of NADPH oxidases for human cardiovascular disease are based on indirect treatment studies. Several highly effective cardiovascular drugs, such as statins, peroxisome proliferator-activated receptor-␥ agonists, angiotensinconverting enzyme inhibitors, and angiotensin II type 1 (AT 1 ) receptor antagonists prevent the activation or induction of NADPH oxidases and reduce the oxidative burden in patients. 4,5 The possible conclusion that NADPH oxidases are excellent cardiovascular drug targets might, however, still be premature, in particular, in light of the failures of large prospective trials testing antioxidants. 6 These studies demonstrated that, although effective in the acute se...

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Endothelial Cells Negatively Modulate Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells

Cited by 37 publications

References 48 publications

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

The role of oxidative stress in the pathophysiology of hypertension

Vascular Functions of NADPH Oxidases

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