Heme Oxygenase-1

Wenzel, Philip; Oelze, Matthias; Coldewey, Meike; Hortmann, Marcus; Seeling, Andreas; Hink, Ulrich; Mollnau, Hanke; Stalleicken, Dirk; Weiner, Henry; Lehmann, Jochen; Li, Huige; Förstermann, Ulrich; Münzel, Thomas; Daiber, Andreas

doi:10.1161/atvbaha.107.143909

Cited by 78 publications

(40 citation statements)

References 37 publications

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“…In animals, PETN was even reported to prevent endothelial dysfunction and atherogenesis in animal models of atherosclerosis. 81 The peculiar properties of this drug, including its capacity to induce the antioxidant defense protein heme oxygenase-1 and to increase the expression and production of ferritin, of the antioxidant molecule bilirubin, and of the vasodilator carbon monoxide 82 have been investigated recently by our group 83,84 ( Figure 8). …”

Section: Are All Nitrates Homogeneous In the Induction Of Tolerance Amentioning

confidence: 99%

Nitrate Therapy

2011

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A lthough the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion 1 as well as specific vascular changes such as increased vascular superoxide (O 2 ·Ϫ ) production, 2 increased sensitivity to vasoconstrictors, 3 and decreased responsiveness to nitric oxide (NO) donors 4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focused on the concept that an inappropriate production of reactive oxygen species (ROS), an impairment in the scavenging of these mediators (Figure 1), or both might have a crucial mechanistic importance in all these modifications. 6,7 Independently of the role of ROS in tolerance, the possibility that nitrate-induced oxidative stress might affect patients' prognosis has important implications, and the observation that long-term therapy with most of the drugs in this class causes endothelial dysfunction, the prognostic significance of which is well accepted in patients with coronary artery disease, hypertension, and heart failure, 8 should not be taken as an academic curiosity.Beyond these as-yet insufficiently investigated prognostic implications, recognition of the role of ROS suggests that a number of interventions thought to interfere with the vascular redox balance might also retard or prevent the development of nitrate tolerance and nitrate-induced side effects. Evidence that therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor blockers, certain ␤-blockers, statins, and vitamins such as folic acid or vitamin C beneficially influence nitrate tolerance and glyceryl trinitrate (GTN)-induced endothelial dysfunction suggests that nitrate therapy might have profoundly different implications since these therapies have become diffusely available. In addition, the recognition of important differences in the mechanisms triggered by different nitrates should also be attributed clinical relevance, and evidence suggests that, rather than the generic nitrate tolerance, more specific expressions (GTN tolerance, isosorbide mononitrate [ISMN] tolerance, etc) should be used. 9 This review summarizes the current concepts underlying tolerance and endothelial dysfunction in response to longterm therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects. The Hemodynamic Effects of NitratesVenous capacitance vessels, large and medium-sized coronary arteries, and collateral vessels are most sensitive to GTN, whereas coronary and peripheral arterioles with a diameter Ͻ100 m are relatively more resistant. In the setting of stable angina, the preferential venodilatation induced by antiischemic doses of GTN results in venous pooling an...

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Section: Are All Nitrates Homogeneous In the Induction Of Tolerance Amentioning

confidence: 99%

Nitrate Therapy

2011

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“…PETN protects against endothelial dysfunction and vascular oxidative stress, largely via HO-1-dependent mechanism. [10][11][12][13][14][15] In this study, we provided novel evidence that upregulation of the antioxidant enzyme HO-1 contributed to PETN-mediated cytoprotective effect by inhibiting mitochondrial ROS generation and NOX4 expression. Previous studies have reported that NOX4-dependent O 2…”

Section: Discussionmentioning

confidence: 75%

“…10,11 PETN has been shown to protect against endothelial dysfunction and vascular oxidative stress. [12][13][14][15] Potential effects of PETN treatment in congestive heart failure (CHF) have not been studied yet. Therefore, we investigated the effects of long-term treatment with PETN on progressive cardiac remodeling (dilation and cellular and molecular dysregulations) in CHF rats after extensive myocardial infarction (MI).…”

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Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

et al. 2015

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Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.

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“…We employed the L-012 ECL assay for measuring mitochondrial peroxynitrite formation in nitrate tolerance induced by nitroglycerin in rats [39,[112][113][114][115][116][117] or mice [56,118,119]. In these publications L-012 ECL signals correlated well with 3-nitrotyrosine levels in mitochondria of various tissues upon in vitro and in vivo nitroglycerin treatment, with ROS and RNS detection by other assays such as HPLC-based 2-hydroxyethidium measurement or dihydrorhodamine fluorescence, inhibition of the redox-sensitive enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) and other markers of oxidative stress such as products of lipid peroxidation or 8-oxo-G and was improved by various antioxidant therapies (reviewed in [120]).…”

Section: L-012-based Whole Blood Chemiluminescence Assay (L-012 Oxidamentioning

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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Heme Oxygenase-1

Cited by 78 publications

References 37 publications

Nitrate Therapy

Nitrate Therapy

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

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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