scholarly journals Parathyroid Hormone Causes Endothelial Dysfunction by Inducing Mitochondrial ROS and Specific Oxidative Signal Transduction Modifications

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
Jessica Gambardella ◽  
Matteo De Rosa ◽  
Daniela Sorriento ◽  
Nella Prevete ◽  
Antonella Fiordelisi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin D ◽  
Parathyroid Hormone ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mitochondrial Calcium ◽  
Calcium Fluxes ◽  
Mitochondrial Ros ◽  
Endothelial Response ◽  
Underlying Mechanisms

Vitamin D deficiency contributes to cardiovascular risk (CVR), with hyperparathyroidism advocated as a putative mechanism. Indeed, mounting evidence supports the hypothesis that parathyroid hormone (PTH) impairs endothelial function, even though mechanisms are not fully elucidated. The present study was designed to verify in vitro the ability of sustained exposure to PTH to cause endothelial dysfunction, exploring the underlying mechanisms. In bovine aortic endothelial cells (BAECs), we evaluated the effects of PTH exposure (0.1 nM–24 hours) on both endothelial response to vasodilators, such as bradykinin (Bk (30 nM)) and acetylcholine (Ach (1 μM)), and angiogenic competence. Pretreatment with PTH impaired endothelial response to Bk but not to Ach, in terms of cytosolic calcium fluxes and NO production. In order to explore the underlying mechanisms, we assessed the production of total and mitochondrial ROS (tROS and mROS, respectively) in response to PTH (at 1 and 3 hours). PTH increased ROS generation, to an extent high enough to determine oxidation of Bk receptor B2. Conversely, the oxidation levels of M1 and M3 Ach receptors were not affected by PTH. A mROS selective scavenger (MitoTEMPO (5 μM)) restored the endothelial responsiveness to Bk while the well-known antioxidant properties of vitamin D (100 nM) failed to counteract PTH-mediated oxidative stress. PTH determined mitochondrial calcium fluxes ([Ca2+]mt) and the mitochondrial calcium uniporter inhibitor Ru360 (10 μM) reduced mROS production and prevented the PTH-mediated endothelial dysfunction. Angiogenic competence was evaluated as tubular formations in the endothelial Matrigel assay and showed a significant impairment in PTH-pretreated cells (0.1 nM–24 hours), despite the increase in VEGF transcriptional levels. VEGFR2 oxidation occurred in response to PTH, suggesting that even the impairment of angiogenesis was due to the ROS surge. These results indicate that PTH affects endothelial function through ROS production, driven by mitochondrial calcium overload. PTH-induced oxidative stress might act as signaling modifiers, altering specific pathways (Bk and VEGF) and preserving others (Ach).

scholarly journals Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Sebastian Steven ◽  
Matthias Oelze ◽  
Moritz Brandt ◽  
Elisabeth Ullmann ◽  
Swenja Kröller-Schön ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Whole Blood ◽  
Pulmonary Arteries ◽  
Vascular Wall ◽  
Pentaerythritol Tetranitrate ◽  
Endothelin 1 ◽  
Pulmonary Arterial

Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined.Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells.Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

Role of EGFR/ErbB2 and PI3K/AKT/e-NOS in Lycium barbarum polysaccharides Ameliorating Endothelial Dysfunction Induced by Oxidative Stress

2019 ◽  
Vol 47 (07) ◽  
pp. 1523-1539 ◽  
Author(s):  
Wenjuan Zhang ◽  
Huifang Yang ◽  
Lingqin Zhu ◽  
Yan Luo ◽  
Lihong Nie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Cell Viability ◽  
Therapeutic Option ◽  
Critical Role ◽  
Ang Ii ◽  
Lycium Barbarum ◽  
Underlying Mechanisms ◽  
Lycium Barbarum Polysaccharides

Lycium barbarum polysaccharides (LBP) are the major ingredients of wolfberry. In this study, we investigated the role of LBP in endothelial dysfunction induced by oxidative stress and the underlying mechanisms using thoracic aortic endothelial cells of rat (RAECs) as a model. We found that Ang II inhibits cell viability of RAECs with 10[Formula: see text][Formula: see text]mol/L of Ang II treatment for 24[Formula: see text]h most potential ([Formula: see text]), the level of reactive oxygen species (ROS) is increased by Ang II treatment ([Formula: see text]), and the expression of Occludin and Zonula occludens-1 (ZO-1) is decreased by Ang II treatment ([Formula: see text]). However, preincubation of cells with LBP could inhibit the changes caused by Ang II, LBP increased cell viability ([Formula: see text]), decreased the level of ROS ([Formula: see text]), and up-regulated the expression of Occludin ([Formula: see text]) and ZO-1. In addition, Ang II treatment increased the expression of EGFR and p-EGFR (Try1172) and which can be inhibited by LBP. On the contrary, expression of ErbB2, p-ErbB2 (Try1248), PI3K, p-e-NOS (Ser1177) ([Formula: see text]), and p-AKT (Ser473) ([Formula: see text]) was inhibited by Ang II treatment and which can be increased by LBP. Treatment of the cells with inhibitors showed that the regulation of p-e-NOS and p-AKT expression by Ang II and LBP can be blocked by PI3K inhibitor wortmannin but not EGFR and ErbB2 inhibitor AC480. Taken together, our results suggested that LBP plays a critical role in maintaining the integrality of blood vessel endothelium through reduced production of ROS via regulating the activity of EGFR, ErbB2, PI3K/AKT/e-NOS, and which may offer a novel therapeutic option in the management of endothelial dysfunction.

Molecular Mechanisms of Endothelial Dysfunction in the Insulin-Resistant State: the Roles of Abnormal Pteridine Metabolism

Pteridines ◽  
2003 ◽  
Vol 14 (1) ◽  
pp. 13-16
Author(s):  
Kazuya Shinozaki ◽  
Atsunori Kashiwagi ◽  
Masahiro Masada ◽  
Tomio Okamura
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Molecular Mechanisms ◽  
No Synthase ◽  
Oral Supplementation ◽  
Insulin Resistant ◽  
Underlying Mechanisms ◽  
Vascular Oxidative Stress ◽  
Resistant State ◽  
Insulin Resistant State

Abstract Although abnormalities in endothelial function are described in various insulin-resistant conditions, including obesity, diabetes, and hypertension in both humans and animal models, the underlying mechanisms are poorly understood. Experimental evidence suggests that (6R)-5,6,7,8-tetrahydrobiopterin (BH4), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS bat also in Controlling the formation of superoxide anion (O2 ) in endothelial cells. Under insulin-resistant conditions where BH4 levels are suboptimal, the production of O2 by NO synthase leads to endothelial dysfunction. Furthermore, oral supplementation of BH4 (10 mg/kg/day) for 8 weeks restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of eNOS in the aorta of insulin-resistant rats. These results suggest that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin-resistant State.

scholarly journals MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure

2010 ◽  
Vol 298 (5) ◽  
pp. H1600-H1607 ◽  
Author(s):  
Jordan D. Miller ◽  
Veronica A. Peotta ◽  
Yi Chu ◽  
Robert M. Weiss ◽  
Kathy Zimmerman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Manganese Superoxide Dismutase ◽  
Reduced Ejection Fraction ◽  
Manganese Superoxide ◽  
Cox Inhibitor

Endothelial function is impaired by oxidative stress in chronic heart failure (HF). Mechanisms that protect against increases in oxidative stress in HF are not clear. The goal of this study was to determine whether manganese superoxide dismutase (MnSOD) plays a key role in protecting against endothelial dysfunction in HF. Endothelial function and gene expression were examined in aorta from wild-type mice (MnSOD+/+) and mice deficient in MnSOD (MnSOD+/−) 12 wk after ligation of the left coronary artery (LCA). LCA ligation produced similar size myocardial infarctions in MnSOD+/+ and MnSOD+/− mice and reduced ejection fraction to ∼20% in both groups. Maximal relaxation in response to acetylcholine was 78 ± 3% (mean ± SE) and 66 ± 8% in sham-operated MnSOD+/+ and MnSOD+/− mice, respectively. Expression of antioxidant enzymes increased in MnSOD+/+ mice with HF, and maximal relaxation to acetylcholine was slightly impaired (68 ± 4%). Greater endothelial dysfunction was observed in MnSOD+/− mice with HF (46 ± 5%, P < 0.05), which was significantly improved by polyethylene glycol-catalase but not Tempol. Incubation with the nonspecific cyclooxygenase (COX) inhibitor indomethacin or the COX1 inhibitor valeryl salicylate, but not the COX-2 inhibitor NS-398, significantly improved relaxation to acetylcholine in HF mice (maximum relaxation = 74 ± 5, 91 ± 1, and 58 ± 5%). These data suggest that MnSOD plays a key role in protecting against endothelial dysfunction in HF. A novel mechanism was identified whereby chronic increases in oxidative stress, produced by mitochondrial SOD deficiency, impair vascular function via a hydrogen peroxide-dependent, COX1-dependent, endothelium-derived contracting factor.

scholarly journals Genderspecific differences of homocysteinemia and its influence on oxidative stress parameters and endothelial function in patients with stable forms of coronary heart disease

2017 ◽  
Vol 95 (8) ◽  
pp. 705-712
Author(s):  
Olga L. Belaya ◽  
K. Yu. Bondar ◽  
L. I. Markova ◽  
Z. V. Kuropteva ◽  
L. M. Baider ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Gas Liquid Chromatography ◽  
Men And Women ◽  
Stable Forms ◽  
Gender Specific

One of the early manifestations of atherosclerotic lesions is endothelial dysfunction developing under conditions of reduced nitric oxide production, hyperhomocysteinemia, and oxidative stress. Bearing in mind high interest shown to gender-specific peculiarities of cardiovascular diseases, it appears important to study the relationship between these features in men and women with stable forms of coronary heart disease (CHD). Material and methods. The study included 102 patients with sable COPD divided into 2 groups (men and women) and 40 practically healthy subjects. Plasma homocysteine levels were measured by high-resolution gas-liquid chromatography with fluorescent detector with the use of Eko-Novo Milikhrom A-02 apparatus (Russia). Standard methods were used to measure plasma lipids, products of their peroxidation (dienic conjugates and products reacting with 2-thibarbituric acid), antioxidant enzymes (glutathioneperoxidase, and superoxide dismutase in erythrocytes), activity of the ceruloplasmin-transferrin system (by electron paramagnetic resonance method), final metabolites of nitric oxide using the Gries reaction. The endothelial function was studies by ultrasound with the evaluation of endothelium-dependent vasodilation. Results. The mean levels of homocystein and final NO metabolites in men with stable CHD were 1.5 times higher (р=0,01) and 12% lower (р = 0,03) than in women. Endothelial dysfunction was more pronounced in men (р< 0,05). Conclusion. Patients with CHD exhibit significant gender-specific differences in blood levels of of homocystein and final NO metabolites as well as in endothelium-dependent vasoreactivity associated with intensification of lipid peroxidation and impairment of antioxidative protection.

Protective Effects of Pomegranate in Endothelial Dysfunction

2020 ◽  
Vol 26 (30) ◽  
pp. 3684-3699 ◽  
Author(s):  
Nathalie T.B. Delgado ◽  
Wender N. Rouver ◽  
Roger L. dos Santos
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Common Factor ◽  
Blood Lipid ◽  
Punica Granatum ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Anti Inflammatory

Background: Punica granatum L. is an infructescence native of occidental Asia and Mediterranean Europe, popularly referred to as pomegranate. It has been used in ethnomedicine for several applications, including the treatment of obesity, inflammation, diabetes, and the regulation of blood lipid parameters. Thus, pomegranate has been linked to the treatment of cardiovascular diseases that have endothelial dysfunction as a common factor acting mainly against oxidative stress due to its high polyphenol content. Its biocomponents have antihypertensive, antiatherogenic, antihyperglycemic, and anti-inflammatory properties, which promote cardiovascular protection through the improvement of endothelial function. Methods: Different electronic databases were searched in a non-systematic way to uncover the literature of interest. Conclusion: This review article presents updated information on the role of pomegranate in the context of endothelial dysfunction and cardiovascular diseases. We have shown that pomegranate, or rather its components (e.g., tannins, flavonoids, phytoestrogens, anthocyanins, alkaloids, etc.), have beneficial effects on the cardiovascular system, improving parameters such as oxidative stress and the enzymatic antioxidant system, reducing reactive oxygen species formation and acting in an anti-inflammatory way. Thus, this review may contribute to a better understanding of pomegranate's beneficial actions on endothelial function and possibly to the development of strategies associated with conventional treatments of cardiovascular diseases.

Abstract P182: Advanced Atherosclerosis is Associated with Systemic and End-organ Inflammation, Vascular Oxidative Stress and Endothelial Dysfunction but not Hypertension in Mice

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Quynh N Dinh ◽  
Grant R Drummond ◽  
Henry Diep ◽  
Christopher T Chan ◽  
Dorota Ferens ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
High Fat ◽  
Chronic Inflammatory Condition ◽  
Tnf Α ◽  
Brain Expression ◽  
Cytokine Levels ◽  
Ifn Γ ◽  
Vascular Oxidative Stress

Introduction: Evidence suggests that hypertension involves underlying inflammation, however whether atherosclerosis - a chronic inflammatory condition - can cause hypertension is unknown. We tested whether blood pressure (BP) is higher in high-fat fed ApoE-/- vs chow-fed wild-type (WT) mice, and whether advanced atherosclerosis is associated with systemic and end-organ inflammation, oxidative stress and endothelial dysfunction. Methods: Male ApoE-/- and WT mice were placed on high fat and chow diets, respectively, from 5-56 weeks. To clarify the effects of ageing alone, aged WT mice were compared to young chow-fed WT mice (8-12 week old). We measured systolic BP, plasma cytokine levels, mRNA expression of inflammatory markers, vascular superoxide and endothelial function. Results: There was no difference in BP of aged ApoE-/- (104.2 ± 2.9 mmHg) and age-matched WT mice (113.2 ± 1.3 mmHg) (n=13-18, P>0.05). However, plasma IL-6, TNF-α and IFN-γ were elevated in ApoE-/- by more than 2-fold vs age-matched WT (n=9-10, all P<0.05), as was brain expression of IL-1β, IL-6, TNF-α, IFN-γ, TGFβ1, CCR2, CCL2, CCL7, CCL8, CCL12 and IL-10 (n=9-10, all P<0.05), and aortic expression of IL-6, CCR2, CCL8 and CCL12 (n=6-8, all P<0.05). Ageing, but not atherosclerosis, increased renal expression of IL-1β, IL-6, TNF-α, CCR2, CCL2, CCL7, CCL8, CCL12 and Foxp3, and aortic expression of CCL2, IL-10 and Foxp3 by at least 2-fold (n=6-10, all P<0.05). In ApoE-/- aorta, Nox2-dependent superoxide production was 4-fold greater than in WT (n=5-6, P<0.05), and endothelium-dependent vasorelaxation to carbachol was markedly reduced by more than half (n=5-7, P<0.05). Ageing alone had no effect on BP, systemic inflammation or endothelial function. Conclusions: Despite the systemic and end-organ inflammation, oxidative stress and endothelial dysfunction, advanced atherosclerosis does not result in elevated BP.

scholarly journals Antioxidant Treatment Reverts Increased Arterial Basal Tone and Oxidative Stress in Nephrectomized (5/6) Hypertensive Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Rodrigo O. Marañón ◽  
Claudio Joo Turoni ◽  
Maria Sofia Karbiner ◽  
Nicolas Salas ◽  
Maria Peral de Bruno
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Basal Tone ◽  
No Bioavailability

Nonischemic 5/6 nephrectomized rat (NefR) is a model of chronic kidney disease. However, little is known about vascular dysfunction and its relation with hypertension in NefR.Aims. To evaluate possible alterations of endothelial function, NO-bioavailability, and basal tone in aorta from NefR and the role of oxidative stress. Sprague Dawley rats were divided into sham rats (SR), NefR, and NefR treated with tempol (NefR-T). Mean arterial pressure (MAP) and renal function were determined. In isolated aortic rings the following was measured: 1-endothelial function, 2-basal tone, 3-NO levels, 4-membrane potential (MP), and 5-oxidative stress. NefR increased MAP (SR: 119 ± 4 mmHg;n=7; NefR: 169 ± 6;n=8;P<0.001). Tempol did not modify MAP (NefR-T: 168 ± 10;n=6;P<0.001). NefR showed endothelial dysfunction, increased basal tone and decreased NO levels (SR: 32 ± 2 nA;n=7, NefR: 10 ± 2;n=8;P<0.001). In both in vitro and in vivo tempol improves basal tone, NO levels, and MP. Oxidative stress in NefR was reverted in NefR-T. We described, for the first time, that aorta from NefR presented increased basal tone related to endothelial dysfunction and decreased NO-bioavailability. The fact that tempol improves NO-contents and basal tone, without decrease MAP, indicates that oxidative stress could be implicated early and independently to hypertension, in the vascular alterations.

scholarly journals Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade?

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S64-S69 ◽  
Author(s):  
Lodewijk J Wagenaar ◽  
Hendrik Buikema ◽  
Yigal M Pinto ◽  
Wiek H van Gilst
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Candesartan Cilexetil ◽  
Ace Inhibition ◽  
At1 Receptor ◽  
Converting Enzyme Inhibitors ◽  
Raas Blockade

Chronic heart failure (CHF) is associated with endothelial dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) is believed to be important in the deterioration of endothelial dysfunction in CHF through stimulation of oxidative stress. Whereas angiotensin-converting enzyme inhibitors (ACE-I) improve endothelial function in CHF, the effects of angiotensin II AT1-receptor blockers (ARB) are less well established. Therefore we compared the effects of the ACE-I lisinopril vs. the ARB candesartan on endothelial dysfunction in a rat model of CHF. CHF was induced by myocardial infarction (MI) after coronary ligation. Two weeks after MI, daily treatment with lisinopril (2 mg/kg) or candesartan cilexetil (1.5 mg/kg) was started. After 13 weeks, rats were sacrificed and endothelial function was determined by measuring acetylcholine (ACh)-induced vasodilation in aortic rings, with selective presence of the nitric oxide synthase (NOS)-inhibitor NG-monomethyl-L-arginine (L-NMMA) to determine the contribution of nitric oxide (NO). ACh-induced vasodilation was attenuated in untreated MI (-50%) compared with control rats. This was in part due to an impaired contribution of NO (-49%). Lisinopril and candesartan cilexetil fully normalised ACh-induced dilation, including the part mediated by NO. Chronic RAAS-blockade with lisinopril and candesartan cilexetil normalised endothelial function in CHF in a comparable way. The effect of both treatments included the increase of the NO-mediated dilation, further indicating the important role of oxidative stress in the relationship between the RAAS and endothelial dysfunction in CHF.

Sign in / Sign up

Export Citation Format

Share Document