Targeting vascular (endothelial) dysfunction

Daiber, Andreas; Steven, Sebastian; Weber, Alina; Shuvaev, Vladimir V.; Muzykantov, Vladimir R.; Laher, Ismail; Li, Huige; Lamas, Santiago; Münzel, Thomas

doi:10.1111/bph.13517

Cited by 401 publications

(402 citation statements)

References 378 publications

(427 reference statements)

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“…2E), which is best explained by direct oxidative inactivation of the constituents of this pathway (e.g. thiol oxidation in sGC, oxidative break-down of • NO, and oxidative depletion of BH4) [56,57] but also adverse phosphorylation of eNOS at Thr495 by protein kinase C [40,41]. Our ChIP data on histone modification at the eNOS promoter show that the activating H3K4me3 mark is decreased throughout all ZDF groups and not restored by SGLT2i treatment supporting that improved…”

Section: Discussionmentioning

confidence: 60%

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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Section: Discussionmentioning

confidence: 60%

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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“…In contrast, several small cohort trials using in most cases acute (short-term) and high dose administration (e.g. via infusion) of antioxidants such as vitamin C demonstrated a highly beneficial action in various diseases including arterial hypertension, diabetes mellitus and in chronic smokers (reviewed in [12,17]). …”

Section: Reactive Oxygen and Nitrogen Species Formation Redox Biologmentioning

confidence: 99%

“…Oxidative stress is a major trigger of endothelial dysfunction and manifest cardiovascular disease [17]. Therefore, the precise determination of reactive oxygen and nitrogen species formation is of great importance for the evaluation of disease mechanisms and potential therapeutic drug targets.…”

Section: State-of-the-art and Cutting-edge Ros And Rns Detection Assamentioning

confidence: 99%

“…The cutting edge and future techniques comprise ROS-induced formation of microbubbles that are detected by ultra sound and can be used in living animals or even humans (reviewed in [17]). A study in mice used ultrasound to measure the reaction of ROS with liposomeencapsulated allylhydrazine, a liquid compound, that yields nitrogen and propylene gas that is detected by ultrasound methods [153].…”

Section: No the Reaction Ofmentioning

confidence: 99%

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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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“…6 | P a g e increased circulatory levels of vasoconstrictors and inflammation (Csiszar et al, 2004;Daiber et al, 2016). Today, it is widely accepted that OS plays a pivotal role in age-related endothelial dysfunction (Brandes et al, 2005).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The effects of resveratrol on aging vessels

Díaz

Degens

Vanhees

et al. 2016

Experimental Gerontology

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Aging is a major risk factor for the development of cardiovascular disease. Despite a significant reduction in the mortality and morbidity rates over the last decade, the socio-economic burden of cardiovascular disease is still substantial. Consequently, there is a considerable need for alternative strategies, such as nutraceutical supplementation, that delay the functional vascular decline present in the elderly.Compromised autophagy and oxidative stress (OS) are considered major causes of the age-related endothelial dysfunction. OS reduces the bioavailability of nitric oxide (NO), which has been associated with hypertension, arteriosclerosis and a reduced vasodilatory response. High levels of free radicals and the low bioavailability of NO lead to a positive feedback loop of further OS, organelle damage, poor repair and endothelial dysfunction. Here we draw attention to the relationship between OS and autophagy in the aged vasculature. We have reviewed the published literature and provided arguments that support that treatment with resveratrol stimulates autophagy and thereby has the potential to restore oxidative balance in the endothelium, which indicates that treatment with resveratrol might have therapeutic potential to restore endothelial function in the elderly.

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Targeting vascular (endothelial) dysfunction

Abstract: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

Cited by 401 publications

References 378 publications

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

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

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

The effects of resveratrol on aging vessels

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