AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats

Wenzel, Philip; Schulz, Eberhard; Oelze, Matthias; Müller, Johanna; Schuhmacher, Swenja; Alhamdani, Mohamed Saiel Saeed; Debrezion, Johannes; Hortmann, Marcus; Reifenberg, Kurt; Fleming, Ingrid; Münzel, Thomas; Daiber, Andreas

doi:10.1016/j.freeradbiomed.2008.05.009

Cited by 110 publications

(124 citation statements)

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“…We aimed to exploit the ability of this drug to inhibit the production of superoxide radicals by mitochondrial NADPHdependent oxidase and xanthine oxidase (15), and to, at least partially, antagonize PPAR-γ activation (16). In this earlier study, we reported that TEL was able to reduce EPI-induced oxidative stress/chronic inflammation and to reverse early myocardial impairment (14).…”

Section: Introductionmentioning

confidence: 99%

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

Dessì

Piras

Madeddu

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular diseasefree with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were determined. All assessments were carried out at baseline, after every 100 mg/m 2 of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t 2 (cumulative dose of 200 mg/m 2 of EPI) in comparison to t 0 . Conversely, at t 3 (300 mg/m 2 EPI), t 4 (400 mg/m 2 EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t 0 (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m 2 EPI (t 3 ) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m 2 EPI (t 2 ) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t 2 vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t 2 was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t 2 in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress. IntroductionAnthracyclines (ANTs) are among the most effective anticancer drugs used in the treatment of a wide spectrum of malignancies. Regrettably, their clinical use is limited by the occurrence of dose-related cardiotoxicity (4).Several studies have shown that chemotherapy-induced cardiotoxicity (CTX) produced by ANTs is at least partially mediated by chronic inflammation and oxidative stress, with proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) (2) playing a central role (5,6). It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane,

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Section: Introductionmentioning

confidence: 99%

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

Dessì

Piras

Madeddu

et al. 2011

Experimental and Therapeutic Medicine

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“…The DHE cryo staining assay yielded reliable increases in signal intensity in tissues from numerous animal disease models but also human samples: diabetes mellitus in rat [36,37] To determine eNOSdependent ROS formation, vessels were preincubated with the NOS inhibitor L-NAME (500 µM, lower panel), embedded in Tissue Tek resin, frozen, cryo-sectioned, and stained with DHE (1 µM) [23]. It should be noted that DHE does not react with "accumulated" ROS (most likely superoxide) in the cryo-sections, which would have been decomposed during storage, but DHE is oxidized by de novo formed ROS coming from uncoupled eNOS or NADPH oxidase after freezing and thawing.…”

Section: Dihydroethidium Oxidative Fluorescence Microtopography (Dhe mentioning

confidence: 99%

“…These are only selected references since in total we have successfully used the DHE (cryo) staining assay in more than 70 original publications with all kinds of pharmacological interventions of genetic manipulation of redox pathways (for summary see [1,10,34]. The DHE (cryo) staining intensity always nicely correlated with the severity of the respective phenotype, was reduced by pharmacological therapy [22,23,36,43,45,48,53] or genetic deletion of the Nox subunit p47 phox [54] and aggravated by genetic deletion of protective antioxidant enzymes such as heme oxygenase-1, manganese superoxide dismutase or glutathione peroxidase-1 [49,55,56] and eliminated by ex vivo incubation with specific superoxide quenchers such as PEG-SOD [53]. It would be a quite surprising coincidence if in all these models, interventions and studies DHE (cryo) staining always would have identified the diseased group where higher oxidative stress levels were shown by other widely accepted methods for ROS and RNS detection, in particular since in all these models reduction in superoxide leels went along with an increase in vascular…”

Section: Dihydroethidium Oxidative Fluorescence Microtopography (Dhe mentioning

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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“…Protein expression and modification was assessed by standard Western and dot blot analysis using established protocols [18,29]. Immunoprecipitation of eNOS was performed with M-280 sheep antimouse IgG coated beads from Invitrogen (Darmstadt, Germany) along with a monoclonal mouse eNOS (Biosciences, USA) antibody [33].…”

Section: Enos Immunoprecipitation Western Blot and Dot Blot Analysismentioning

confidence: 99%

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

Hanf

Steven

Oelze

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance ® ), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF-Lepr fa/fa and 16 ZDF-Lepr +/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).

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AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats

Cited by 110 publications

References 46 publications

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

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

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

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