Functional and Biochemical Analysis of Endothelial (Dys)function and NO/cGMP Signaling in Human Blood Vessels With and Without Nitroglycerin Pretreatment

Schulz, Eberhard; Tsilimingas, Nikolaos; Rinze, Ruth; Reiter, B.; Wendt, Maria; Oelze, Mathias; Woelken-Weckmüller, Silke; Walter, Ulrich; Reichenspurner, Hermann; Meinertz, Thomas; Münzel, Thomas

doi:10.1161/hc1002.105186

Cited by 153 publications

(123 citation statements)

References 33 publications

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“…The elevation of superoxide can limit the bioavilabilty of both endogenous and exogenous NO through the diffusion controlled reaction of superoxide with NO to produce peroxynitrite [23,24]. Peroxynitrite is an oxidizing and nitrating cytotoxin that could contribute to nitrate tolerance through interference with the normal function of nitric oxide synthase or the cyclic GMP-dependent protein kinase [25,26].…”

Section: Discussionmentioning

confidence: 99%

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Tan¹,

Zhang²,

Anyadike³

et al. 2007

Pharmacological Research

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Abstractexposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic GMP. We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3 mg/hr for 5 days). Myocyte function was determined at baseline, after CNP (C-type natriuretic peptide, 10 −8 and 10 −7 M) or BNP (Brain natriuretic peptide, 10 −8 and 10 −7 M) or SNAP (S-nitroso-N-acetyl-penicilliamine, a NO donor, 10 −6 and 10 −5 M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10 −6 M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10 −8 M (5.14±0.5%) and 10 −7 M (4.4±0.7%) significantly reduced percentage shortening from baseline (6.1±1.6%). KT5823 restored percentage shortening to 4.9±0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.

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Section: Discussionmentioning

confidence: 99%

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Tan¹,

Zhang²,

Anyadike³

et al. 2007

Pharmacological Research

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“…In the vascular wall, phosphorylation of VASP at Ser-239 (24) (product denoted P Ser-239 -VASP) is regulated by NO and prostacyclin. Phosphorylation of VASP at Ser-239 is a sensitive monitor of defective vascular NO͞cGMP signaling (25,26), endothelial dysfunction (27,28), and vascular oxidative stress (29).…”

mentioning

confidence: 99%

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Melichar¹

2004

Proceedings of the National Academy of Sciences

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Atherosclerosis is associated with alterations in nitric oxide (NO)͞ cGMP signaling. In early stages of the disease, inflammatory and possibly other cells produce reactive oxygen species that scavenge vasoprotective NO. In addition to the oxidative stress, expression and activity of enzymes downstream to NO formation may also be affected. Here, we show in the aortas of chronically hypercholesterolemic rabbits (a model of late-stage atherosclerosis), both subunits and specific activity of the NO receptor soluble guanylyl cyclase (sGC) were significantly reduced, whereas overall NO synthase activity was unaffected. These changes were most prominent in the neointimal layer, wherein cGMP-dependent protein kinase I (cGK) levels also were reduced. Additionally, a protein (p38 nt ) that was constitutively tyrosine-nitrated was detected, and its expression was significantly reduced in atherosclerotic aorta. Phosphorylation of the cGK substrate vasodilator-stimulated phosphoprotein (VASP) at Ser-239, an established biochemical endpoint of NO͞cGMP signaling, also was reduced. Thus, late-stage atherosclerosis is associated not only with enhanced NO breakdown but also with altered NO reception and cGMP signaling. Preferential downregulation in neointima suggests a direct connection of these changes to neointimal proliferation and vascular dysfunction and provides a rationale for future pharmacotherapy using classical and novel sGC activators.hypercholesterolemia ͉ soluble guanylyl cyclase ͉ vasodilator-stimulated phosphoprotein ͉ cGMP-dependent protein kinase A therosclerosis is major risk factor to cardiovascular diseases such as coronary heart disease and stroke. The pathophysiology of atherosclerosis is highly complex, multifactorial, and yet to be fully understood (1). A common feature observed is malperfusion of tissues as a result of luminally obstructive atherosclerotic plaques, augmented vascular tone, and reduced sensitivity to endothelium-dependent vasodilators in atherosclerotic arteries from humans (2) and cholesterol-fed animals (3).Nitric oxide (NO) is an important antiatherosclerotic autocoid, which exerts antiproliferative and vasodilatory effect on vasculature and antiaggregatory effect on platelets. Vascular dysfunction in atherosclerosis is partly attributed to reduced tetrahydrobiopterin-dependent (4-7) production or bioavailability of endothelium-derived NO (8), which is supported by the observation of reduced activity and expression of endothelial NO synthase III (NOS-III) (9) in atherosclerotic vessels (10, 11). Additionally, the tissue half-life of NO is further reduced by reactive oxygen species (superoxide, O 2 Ϫ ) that scavenge NO and thereby impair its vasoprotective activity (12). Therefore, formation of O 2 Ϫ , by NADPH oxidase (13, 14) or xanthine oxidase (15) or uncoupled endothelial NOS (16) and͞or its decomposition, by superoxide dismutase (SOD) (17)(18)(19), are thought to play important roles in the pathogenesis of atherosclerosis.Endothelium-derived NO stimulates the production of the se...

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“…The method of densitometric quantification of endothelial DHE staining was adopted from a published protocol [68](A-C) Stainings were selected from unused pictures and graphs were drafted de novo from original data published in Schuhmacher et al, Hypertension 2010 [23]. Aortic endothelial DHE staining correlated well with endothelial dysfunction measured by ACh-dependent relaxation using isometric tension recording [62] (D), impaired calcium ionophore-stimulated tolerance in rat [38], mouse [39], rabbits [40] and human [41]; isosorbide-5-mononitrate-induced endothelial dysfunction [26]; cyclooxygenase inhibitor-induced NADPH oxidase activation in rat [42]; atherosclerosis in Watanabe Heritable Hyperlipidemic (WHHL) rabbits [40,43], ApoE knockout [44] and high fat diet fed mice (Steven et al, in revision in Cardiovasc. Res.…”

Section: Dihydroethidium Oxidative Fluorescence Microtopography (Dhe mentioning

confidence: 99%

“…Redox Biology 12 (2017) [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] meaning and can be used in combination with state-of-the-art assays or accepted redox biomarkers (Fig. 4).…”

Section: No the Reaction Ofmentioning

confidence: 99%

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

Daiber

Oelze

Sebastian

et al. 2017

Free Radical Biology and Medicine

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Keywords:Oxidative stress Redox signaling Fluorescence and chemiluminescence-based assays Dihydroethidium oxidative fluorescence microtopography Lucigenin-enhanced chemiluminescence L-012-enhanced chemiluminescence A B S T R A C T Reactive oxygen and nitrogen species (RONS such as H 2 O 2 , nitric oxide) confer redox regulation of essential cellular functions (e.g. differentiation, proliferation, migration, apoptosis), initiate and catalyze adaptive stress responses. In contrast, excessive formation of RONS caused by impaired break-down by cellular antioxidant systems and/or insufficient repair of the resulting oxidative damage of biomolecules may lead to appreciable impairment of cellular function and in the worst case to cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, the knowledge of the severity of oxidative stress and tissue specific localization is of great biological and clinical importance. However, at this level of investigation quantitative information may be enough. For the development of specific drugs, the cellular and subcellular localization of the sources of RONS or even the nature of the reactive species may be of great importance, and accordingly, more qualitative information is required. These two different philosophies currently compete with each other and their different needs (also reflected by different detection assays) often lead to controversial discussions within the redox research community. With the present review we want to shed some light on these different philosophies and needs (based on our personal views), but also to defend some of the traditional assays for the detection of RONS that work very well in our hands and to provide some guidelines how to use and interpret the results of these assays. We will also provide an overview on the "new assays" with a brief discussion on their strengths but also weaknesses and limitations.

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Functional and Biochemical Analysis of Endothelial (Dys)function and NO/cGMP Signaling in Human Blood Vessels With and Without Nitroglycerin Pretreatment

Cited by 153 publications

References 33 publications

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

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