Endothelins and Nadph Oxidases in the Cardiovascular System

Dammanahalli, Karigowda J.; Sun, Zhongjie

doi:10.1111/j.1440-1681.2007.04830.x

Cited by 45 publications

(39 citation statements)

References 65 publications

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“…ET-1 has been shown to impact cell survival, cause cell proliferation, cell migration, reactive oxygen and nitrogen species generation, and is known to stimulate release of inflammatory cytokines, including TNF-␣, IL-6, and mediators such as NFB in a number of cell types (14,19,58,87). These effects are mediated largely via ET A receptors in most cell types.…”

Section: Vascular Effects Of Et-1 Signalingmentioning

confidence: 99%

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

Bourque

Davidge

Adams

2011

American Journal of Physiology-Regulatory, Integrative and Comp

189

143

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are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.ONCE THOUGHT TO BE AN INERT barrier delineating the boundaries of the circulation, the endothelium is now known to be a critical junction of vascular signaling. The endothelium produces and is acted upon by a host of mediators in what appears to be an exceedingly complex and interrelated signalome. With its capacity to release mediators involved in vasoconstriction, vasodilation, cell adhesion, growth, differentiation, proliferation, and motility, normal endothelial function is a prerequisite for cardiovascular health. Indeed, endothelial dysfunction, characterized by altered production of vasoactive substances, often precedes the overt manifestation of disease and is considered an important etiological factor in the progression of cardiovascular diseases.Endothelin-1 (ET-1) has been known to be an important mediator of vascular function since its discovery by Yanagisawa et al. in the late 1980's (106). Due to its potent and long-lasting vasoconstrictor effects, its capacity to induce vascular remodeling, fibrosis, cell proliferation, apoptosis, and its link to oxidative stress, ET-1 has been proposed to be important in the progression of numerous pathologies (51). The recognition of its importance in cardiovascular disease is perhaps best illustrated by the observation of Barton and Yanagisawa that within 4 years of ET-1's discovery, its receptors had been cloned and pharmacological antagonists had been developed; these therapeutics were being tested in clinical trials by the early 1990's (8). However, despite intensive study over the past two decades and the relative success of ET-1 antagonists in certain conditions [e.g., pulmonary hypertension (71), congestive heart failure (83)], the precise role of ET-1 in vascular physiology and pathophysiology has stubbornly eluded investigators. This may be due, in part, to several intricacies of the ET-1 system that makes it inherently complex [e.g., receptor localization, receptor dimerization (100)].Notwithstanding these difficulties, ET-1, like many vascular mediators, is an intrinsically complicated system by virtue of the fact that its function in physiology and pathophysiology is inextricably linked with other vascular mediators, most notably nit...

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Section: Vascular Effects Of Et-1 Signalingmentioning

confidence: 99%

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

Bourque

Davidge

Adams

2011

American Journal of Physiology-Regulatory, Integrative and Comp

189

143

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“…Recent evidence indicates that ROS are essential for normal lung= endothelial barrier function (76), and an imbalance of the redox equilibrium seems to contribute to pulmonary edema and leakiness (164,165). An explosion has occurred in publications and reviews related to ROS-generating NADPH oxidases in cardiovascular health and disease states (21,43,49,79,147,150,155,200,220), with a limited focus on mechanisms of regulation. In this review, we address the Nox family of NADPH oxidase as a potential source of ROS involved in lung injury and regulation of endothelial NADPH oxidase activation by protein kinases, phospholipases, and the cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

Regulation of NADPH Oxidase in Vascular Endothelium: The Role of Phospholipases, Protein Kinases, and Cytoskeletal Proteins

Pendyala¹,

Usatyuk²,

Горшкова³

et al. 2009

Antioxidants & Redox Signaling

109

108

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The generation of reactive oxygen species (ROS) in the vasculature plays a major role in the genesis of endothelial cell (EC) activation and barrier function. Of the several potential sources of ROS in the vasculature, the endothelial NADPH oxidase family of proteins is a major contributor of ROS associated with lung inflammation, ischemia=reperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury. The NADPH oxidase in lung ECs has most of the components found in phagocytic oxidase, and recent studies show the expression of several homologues of Nox proteins in vascular cells. Activation of NADPH oxidase of nonphagocytic vascular cells is complex and involves assembly of the cytosolic (p47 phox , p67 phox , and Rac1) and membrane-associated components (Noxes and p22 phox ). Signaling pathways leading to NADPH oxidase activation are not completely defined; however, they do appear to involve the cytoskeleton and posttranslation modification of the components regulated by protein kinases, protein phosphatases, and phospholipases. Furthermore, several key components regulating NADPH oxidase recruitment, assembly, and activation are enriched in lipid microdomains to form a functional signaling platform. Future studies on temporal and spatial localization of Nox isoforms will provide new insights into the role of NADPH oxidase-derived ROS in the pathobiology of lung diseases. Antioxid. Redox Signal. 11, 841-860.

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“…In vivo, intrabrachial infusion of ET-1 during 30 min impairs endothelium-dependent relaxation in healthy men, which can be prevented by coadministration of an antioxidant (13). ET-1 can generate ROS through activation of NADPH oxidase; and conversely, ROS appear to stimulate ET-1 production, leading into a vicious cycle of oxidative stress, inflammation, and vasoconstriction (22). Indeed, among many deleterious effects of increased oxidative stress is rapid consumption of NO in the reaction with superoxide radical, which yields peroxynitrite (ONOO Ϫ ), a reactive nitrating and inflammatory molecule.…”

Section: Endothelin System In Agingmentioning

confidence: 99%

Endothelin in the female vasculature: a role in aging?

Lekontseva

Chakrabarti

Davidge

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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vascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.ET-1; menopause; estrogen; vasoconstriction; inflammation AGING OF THE VASCULAR SYSTEM is a complex process characterized by sustained proinflammatory and proconstrictor changes in the vascular microenvironment. The resulting structural and functional alterations in systemic vasculature lead to increased risk of cardiovascular diseases such as hypertension, myocardial infarction, and stroke in the aging population (12,18,51,70). In the absence of chronic preexisting conditions, such as diabetes, premenopausal women express a favorable cardiovascular phenotype compared with age-matched men, largely due to the vasoprotective role of ovarian steroids such as estrogen (92). An alteration in circulating sex hormones at menopause, such as the decrease in estrogens and a relative excess of androgens, is associated with the conversion from a low-to high-risk cardiovascular profile (19,56). Although the mechanisms underlying the pathogenesis of vascular dysfunction in postmenopausal women are not completely understood, it is believed to result from a complex interplay between the aging process and the decline in ovarian hormones like estrogen.Endothelin has emerged as one of the key mediators of vascular dysfunction and remodeling in aging. Interestingly, there is evidence that female sex steroids (in particular, estrogen) can regulate the endothelin system at various levels from gene transcription and posttranslational modification of the peptide to expression of its vascular receptors and postreceptor signaling events. This review will summarize current knowledge on the impact of aging and female sex hormones on the endothelin system, as well as outline directions where further research is needed. A better understanding of the role of endothelin in the pathogenesis of vascular dysfunction in postmenopausal women may lead to the development of novel sex-...

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Endothelins and Nadph Oxidases in the Cardiovascular System

Cited by 45 publications

References 65 publications

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

Regulation of NADPH Oxidase in Vascular Endothelium: The Role of Phospholipases, Protein Kinases, and Cytoskeletal Proteins

Endothelin in the female vasculature: a role in aging?

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