Browse
Submit Data
Databases
API
Help

Dataset Information

6 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Impact of Oxidative Stress and Protein S-Glutathionylation in Aortic Valve Sclerosis Patients with Overt Atherosclerosis.

ABSTRACT: Aortic valve sclerosis (AVSc) is characterized by non-uniform thickening of the leaflets without hemodynamic changes. Endothelial dysfunction, also caused by dysregulation of glutathione homeostasis expressed as ratio between its reduced (GSH) and its oxidised form (GSSG), could represent one of the pathogenic triggers of AVSc. We prospectively enrolled 58 patients with overt atherosclerosis and requiring coronary artery bypass grafting (CABG). The incidence of AVSc in the studied population was 50%. The two groups (No-AVSc and AVSc) had similar clinical characteristics. Pre-operatively, AVSc group showed significantly lower GSH/GSSG ratio than No-AVSc group (p = 0.02). Asymmetric dimethylarginine (ADMA) concentration was significantly higher in AVSc patients compared to No-AVSc patients (p < 0.0001). Explanted sclerotic aortic valves presented a significantly increased protein glutathionylation (Pr-SSG) than No-AVSc ones (p = 0.01). In vitro, inhibition of glutathione reductase caused β-actin glutathionylation, activation of histone 2AX, upregulation of α2 smooth muscle actin (ACTA2), downregulation of platelet and endothelial cell adhesion molecule 1 (PECAM1) and cadherin 5 (CDH5). In this study, we showed for the first time that the dysregulation of glutathione homeostasis is associated with AVSc. We found that Pr-SSG is increased in AVSc leaflets and it could lead to EndMT via DNA damage. Further studies are warranted to elucidate the causal role of Pr-SSG in aortic valve degeneration.

SUBMITTER: Valerio V

PROVIDER: S-EPMC6517913 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.

Project description:BACKGROUND:Epiaortic ultrasound detects and localizes ascending aortic atherosclerosis. In this analysis we investigated the association between epiaortic ultrasound-based atheroma grade during surgical aortic valve replacement (SAVR) and perioperative adverse outcomes. METHODS:SAVR patients in a randomized trial of 2 embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core laboratory. Aortic atherosclerosis was quantified with the Katz atheroma grade, and patients were categorized as mild (grade I-II) or moderate/severe (grade III-V). Multivariable logistic regression was used to estimate associations between atheroma grade and adverse outcomes, including death, clinically apparent stroke, cerebral infarction on diffusion-weighted magnetic resonance imaging, delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS:Precannulation epiaortic ultrasound data were available for 326 of 383 randomized patients (85.1%). Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. Although differences in the composite of death, stroke, or cerebral infarction on diffusion-weighted magnetic resonance imaging by 7 days were not statistically significant, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio, 2.63; 95% confidence interval, 1.24-5.58; P = .01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke, or AKI (adjusted odds ratio, 1.97; 95% confidence interval, 1.04-3.71; P = .04). CONCLUSIONS:Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events after SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.

| S-EPMC6939455 | biostudies-literature

Aortic Valve Tissue: Stenosis vs. Sclerosis

Project description:We are looking at differential gene/protein expression in tissue from stenotic vs sclerotic human aortic valves in order to identify genetic predispositions for aortic valve disease, as well as novel targets for diagnostic and therapeutic strategies.

2019-10-08 | GSE138531 | GEO

Albumin Thiolation and Oxidative Stress Status in Patients with Aortic Valve Stenosis.

Project description:Recent evidence indicates that reactive oxygen species play an important causative role in the onset and progression of valvular diseases. Here, we analyzed the oxidative modifications of albumin (HSA) occurring on Cysteine 34 and the antioxidant capacity of the serum in 44 patients with severe aortic stenosis (36 patients underwent aortic valve replacement and 8 underwent a second aortic valve substitution due to a degenerated bioprosthetic valve), and in 10 healthy donors (controls). Before surgical intervention, patients showed an increase in the oxidized form of albumin (HSA-Cys), a decrease in the native reduced form (HSA-SH), and a significant reduction in serum free sulfhydryl groups and in the total serum antioxidant activity. Patients undergoing a second valve replacement showed levels of HSA-Cys, free sulfhydryl groups, and total antioxidant activity similar to those of controls. In vitro incubation of whole blood with aspirin (ASA) significantly increased the free sulfhydryl groups, suggesting that the in vivo treatment with ASA may contribute to reducing oxidative stress. We also found that N-acetylcysteine and its amide derivative were able to regenerate HSA-SH. In conclusion, the systemic oxidative stress reflected by high levels of HSA-Cys is increased in patients with aortic valve stenosis. Thiol-disulfide breaking agents regenerate HSA-SH, thus paving the way to the use these compounds to mitigate the oxidative stress occurring in the disease.

| S-EPMC10742097 | biostudies-literature

Aortic Valve Tissue: Stenosis vs. Sclerosis

Project description:Aortic Valve Tissue: Stenosis vs. Sclerosis

| PRJNA576259 | ENA

Endothelial-derived oxidative stress drives myofibroblastic activation and calcification of the aortic valve.

Project description:AimsOxidative stress is present in and contributes to calcification of the aortic valve, but the driving factors behind the initiation of valve oxidative stress are not well understood. We tested whether the valve endothelium acts as an initiator and propagator of oxidative stress in aortic valve disease.Methods and resultsCalcified human aortic valves showed side-specific elevation of superoxide in the endothelium, co-localized with high VCAM1 expression, linking oxidative stress, inflammation, and valve degeneration. Treatment with inflammatory cytokine TNFα increased superoxide and oxidative stress and decreased eNOS and VE-cadherin acutely over 48 hours in aortic valve endothelial cells (VEC) and chronically over 21 days in ex vivo AV leaflets. Co-treatment of VEC with tetrahydrobiopterin (BH4) but not apocynin mitigated TNFα-driven VEC oxidative stress. Co-treatment of ex vivo AV leaflets with TNFα+BH4 or TNFα+peg-SOD rescued endothelial function and mitigated inflammatory responses. Both BH4 and peg-SOD rescued valve leaflets from the pro-osteogenic effects of TNFα treatment, but only peg-SOD was able to mitigate the fibrogenic effects, including increased collagen and αSMA expression.ConclusionsAortic valve endothelial cells are a novel source of oxidative stress in aortic valve disease. TNFα-driven VEC oxidative stress causes loss of endothelial protective function, chronic inflammation, and fibrogenic and osteogenic activation, mitigated differentially by BH4 and peg-SOD. These mechanisms identify new targets for tailored antioxidant therapy focused on mitigation of oxidative stress and restoration of endothelial protection.

| S-EPMC4395382 | biostudies-literature

Sex-and race-specific burden of aortic valve calcification among older adults without overt coronary heart disease: The Atherosclerosis Risk in Communities Study.

Project description:Background and aimsThe prevalence of aortic valve calcification (AVC) increases with age. However, the sex-and race-specific burden of AVC and associated cardiovascular risk factors among adults ≥75 years are not well studied.MethodsWe calculated the sex-and race-specific burden of AVC among 2283 older Black and White adults (mean age:80.5 [SD:4.3] years) without overt coronary heart disease from the Atherosclerosis Risk in Communities Study who underwent non-contrast cardiac-gated CT-imaging at visit 7 (2018-2019). Using Poisson regression with robust variance, we calculated the adjusted prevalence ratios (aPR) of the association of AVC with cardiovascular risk factors.ResultsThe overall AVC prevalence was 44.8%, with White males having the highest prevalence at 58.2%. The prevalence was similar for Black males (40.5%), White females (38.9%), and Black females (36.8%). AVC prevalence increased significantly with age among all race-sex groups. The probability of any AVC at age 80 years was 55.4%, 40.0%, 37.3%, and 36.2% for White males, Black males, White females, and Black females, respectively. Among persons with prevalent AVC, White males had the highest median AVC score (100.9 Agatston Units [AU]), followed by Black males (68.5AU), White females (52.3AU), and Black females (46.5AU). After adjusting for cardiovascular risk factors, Black males (aPR:0.53; 95%CI:0.33-0.83), White females (aPR:0.68; 95%CI:0.61-0.77), and Black females (aPR:0.49; 95%CI:0.31-0.77) had lower AVC prevalence compared to White males. In addition, systolic blood pressure, non-HDL-cholesterol, and lipoprotein (a) were independently associated with AVC, with no significant race/sex interactions.ConclusionsAVC, although highly prevalent, was not universally present in this cohort of older adults. White males had ∼50-60% higher prevalence than other race-sex groups. Moreover, cardiovascular risk factors measured in older age showed significant association with AVC.

| S-EPMC11309802 | biostudies-literature

Impact of low-density lipoprotein cholesterol on progression of aortic valve sclerosis and stenosis.

Project description:BackgroundLittle research has been assessed atherosclerotic risk factors at various stages of calcific aortic valve disease. This study sought to determine risk factors of patients with aortic valve sclerosis (AVS) and mild to moderate aortic stenosis (AS).MethodsThe study included 1,007 patients diagnosed with AVS or mild to moderate AS according to echocardiographic criteria. Patients were identified as a rapid progression group if the annualized difference in peak aortic jet velocity (Vmax) between two echocardiographic examinations was >0.08 m/s/yr in AVS and >0.3 m/s/yr in AS, respectively. We used multivariable logistic regression analyses to assess the factors associated with rapid disease progression or progression to severe AS.ResultsAmong 526 AVS patients, higher LDL-C level (odds ratio [OR] 1.22/per 25 mg/dl higher LDL-C, 95% confidence interval [CI] 1.05-1.43) was significantly associated with rapid disease progression. Compared to patients with LDL-C level <70 mg/dl, the adjusted OR for rapid progression were 1.32, 2.15, and 2.98 for those with LDL-C level of 70-95 mg/dl, 95-120 mg/dl, and ≥120 mg/dl, respectively. Among 481 mild to moderate AS patients, the baseline Vmax (OR 1.79/per 0.5 m/s higher Vmax, 95% CI 1.18-2.70) was associated with rapid progression. Compared to patients with Vmax 2.0-2.5 m/s, the adjusted OR for rapid progression were 2.47, 2.78, and 3.49 for those with Vmax of 2.5-3.0 m/s, 3.0-3.5 m/s, and 3.5-4.0 m/s, respectively. LDL-C and baseline Vmax values were independently associated with progression to severe AS.ConclusionAtherosclerotic risk factors such as LDL-C were significantly associated with the rapid progression in AVS and baseline Vmax was important in the stage of mild to moderate AS.

| S-EPMC10390070 | biostudies-literature

Oxidative stress inhibits vascular K(ATP) channels by S-glutathionylation.

Project description:The K(ATP) channel is an important player in vascular tone regulation. Its opening and closure lead to vasodilation and vasoconstriction, respectively. Such functions may be disrupted in oxidative stress seen in a variety of cardiovascular diseases, while the underlying mechanism remains unclear. Here, we demonstrated that S-glutathionylation was a modulation mechanism underlying oxidant-mediated vascular K(ATP) channel regulation. An exposure of isolated mesenteric rings to hydrogen peroxide (H(2)O(2)) impaired the K(ATP) channel-mediated vascular dilation. In whole-cell recordings and inside-out patches, H(2)O(2) or diamide caused a strong inhibition of the vascular K(ATP) channel (Kir6.1/SUR2B) in the presence, but not in the absence, of glutathione (GSH). Similar channel inhibition was seen with oxidized glutathione (GSSG) and thiol-modulating reagents. The oxidant-mediated channel inhibition was reversed by the reducing agent dithiothreitol (DTT) and the specific deglutathionylation reagent glutaredoxin-1 (Grx1). Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester (BioGEE) showed incorporation of GSH to the Kir6.1 subunit in the presence of H(2)O(2). These results suggest that S-glutathionylation is an important mechanism for the vascular K(ATP) channel modulation in oxidative stress.

| S-EPMC2992296 | biostudies-literature

Altered oxidative stress responses and increased type I collagen expression in bicuspid aortic valve patients.

Project description:BackgroundThe mechanisms governing extracellular matrix degradation and smooth muscle cell (SMC) loss in the ascending aorta of bicuspid aortic valve (BAV) patients are unknown. We recently reported that expression and induction of metallothionein, a reactive oxygen species scavenger, is reduced in BAV ascending aortic aneurysms relative to nonaneurysmal patients.MethodsTissue and primary SMCs from patients with and without thoracic aortic aneurysms and metallothionein-null and wild-type mice were analyzed for cell viability, vascular endothelial growth factor (VEGF), and type I collagen gene expression during exposure to reactive oxygen species.ResultsThe BAV SMCs and metallothionein -/- mice failed to induce VEGF under conditions of oxidative stress in vitro. Exogenous VEGF restored resistance to oxidative stress in BAV SMCs to normal. Type I collagen gene induction was increased in BAV aorta.ConclusionsLack of VEGF induction during exposure to reactive oxygen species suggest that the oxidative stress response is faulty upstream of metallothionein and VEGF in BAV SMCs. Improvement of cell viability with VEGF treatment suggests that the deficient pathway can be rescued by VEGF. Increased type I collagen in BAV suggests that lack of metallothionein/VEGF activation in response to reactive oxygen species may play a role in extracellular matrix homeostasis of the ascending aorta. These data continue to support our hypothesis that BAV SMCs lack sufficient resistance to reactive oxygen species to maintain extracellular matrix homeostasis, which imparts a predisposition to thoracic aortic aneurysms.

| S-EPMC8172083 | biostudies-literature

PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer.

Project description:Whereas moderately increased cellular oxidative stress is supportive for cancerous growth of cells, excessive levels of reactive oxygen species (ROS) are detrimental to their growth and survival. We demonstrated that high ROS levels, via increased oxidized glutathione (GSSG), induce isoform-specific S-glutathionylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) at residue Cys206, which is located near the entrance to the 6-phosphofructo-2-kinase catalytic pocket. Upon this ROS-dependent, reversible, covalent modification, a marked decrease in its catalytic ability to synthesize fructose-2,6-bisphosphate (Fru-2,6-P?), the key glycolysis allosteric activator, was observed. This event was coupled to a decrease in glycolytic flux and an increase in glucose metabolic flux into the pentose phosphate pathway. This shift, in turn, caused an increase in reduced glutathione (GSH) and, ultimately, resulted in ROS detoxification inside HeLa cells. The ability of PFKFB3 to control the Fru-2,6-P? levels in an ROS-dependent manner allows the PFKFB3-expressing cancer cells to continue energy metabolism with a reduced risk of excessive oxidative stress and, thereby, to support their cell survival and proliferation. This study provides a new insight into the roles of PFKFB3 as switch that senses and controls redox homeostasis in cancer in addition to its role in cancer glycolysis.

| S-EPMC3919529 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data