bluuebunny/crossref_metadata_2025_split huggingface dataset:
S-glutathionylation, a redox switch disrupting angiogenic balance to promote the preeclampsia phenotype
Authors: Lermant A , Rabussier G , Sneddon C , Kerr J , Lanz H , Murdoch C E 
Published: October 2021

Abstract

Background
Elevation of circulating anti-angiogenic factors is pivotal in the development of the preeclampsia (PE) phenotype of incomplete vascular remodelling, hypertension and kidney dysfunction during pregnancy. Oxidative stress is explicitly linked to PE with high levels measurable in the placenta. Yet antioxidant therapy has failed, in some cases worsening pregnancy outcomes. The modulation of protein activity by reversible oxidative post-translational modifications (oxPTM) under low levels of reactive oxygen species is emerging as an important “redox-switch” mechanism in cardiovascular diseases, although oxPTM have not been investigated in the context of PE. Of significance, S-glutathionylation is a common oxPTM which reversal by glutaredoxin (Grx) is predominant in preeclamptic placenta and was associated with attenuated revascularisation and sFlt-1 elevation in mice.

Purpose
We aimed to identify the molecular basis for how S-glutathionylation reversal by Grx may contribute to pregnancy-induced vascular complications by modulating angiogenic signalling at the maternofoetal interface.

Methods
We combined physiological in vivo assessment with bioinformatics proteomic analysis and exon-level microarray to investigate the role of S-glutathionylation in the development of PE phenotype. In vitro studies using primary endothelial cells (EC) and iPS-derived trophoblasts investigated the effects of oxPTM reversal on angiogenic signalling in individual placental cell types and the functional consequences were assessed in 3D models replicating early-pregnancy events.

Results
Overexpressing Grx transgenic mice (TG) developed gestational hypertension, kidney dysfunction and elevated plasma levels of the anti-angiogenic factor sFlt-1 compared to their littermate controls (WT) during timed pregnancy. Grx-mediated oxPTM reversal in EC disrupted angiogenic sprouting and promoted anti-angiogenic signals by increasing sFlt-1:PlGF ratio and decreasing endoglin levels. The rise in sFlt-1 was associated with an isoform switch promoting sFlt-e15a over sFlt-i13. In trophoblasts, Grx overexpression inhibited migration and syncytialisation and modulated angiogenic balance in a cell type-specific manner. The sFlt1-e15a:PlGF ratio was increased in syncytiotrophoblasts and decreased in extra-villous trophoblasts, while endoglin expression was decreased in both cell types. A genome-wide exon-level profiling of TG vs WT mice placenta revealed a global alteration of alternative splicing events.

Conclusion
Grx-mediated removal of oxPTM directly disrupts placental angiogenic balance via dysregulation of sFlt-1 isoforms, which may promote the PE phenotype of impaired vascular remodelling, hypertension and kidney dysfunction during pregnancy.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 - Marie Skłodowska-Curie grant agreement (iPLACENTA)
The novel proteomic signature for the detection of cardiac allograft vasculopathy
Authors: Wei D M , Trenson T , Van Keer J M , Melgarejo J , Thijs L , He T L , Latosinska A , Vanassche T , Van Aelst L , Janssens S , Van Cleemput J , Mischak H , Staessen J A , Verhamme P , Zhang Z Y 
Published: October 2021

Abstract

Background
Cardiac allograft vasculopathy (CAV) is the major long-term complications after heart transplantation, leading to mortality and re-transplantation. As available noninvasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV detection.

Methods
Urinary proteome was measured by capillary electrophoresis coupled to mass spectrometry in 217 heart transplantation recipients. Participants were further randomly and evenly divided into the derivation cohort and validation cohort. The proteomic signature for CAV was identified by decision tree-based machine learning in the derivation cohort and further tested in the validation cohort. The pathway analysis was investigated with Reactome Pathway Database.

Results
We identified a proteomic signature with 27 urinary peptides, which yielded areas under the curve (AUC) of 0.83 and 0.71 in the derivation and validation cohort, respectively. In the validation cohort, it had a sensitivity of 68.4%, specificity of 73.2%, accuracy of 71.6%, negative predictive value of 81.3%. Including the proteomic signature into the basic model further improved the diagnostic accuracy with an relative integrated discrimination improvement of 25.9% and the continuous net reclassification improvement of 83.3% (p≤0.023). The pathways analysis on revealed that collagen turnover, platelet aggregation and coagulation, cell adhesion and motility might involve in the pathogenesis of CAV.

Conclusions
The proteomic signature might be valuable for the surveillance of CAV thereby reduce the frequency of invasive procedures after HTx. Moreover, the highlighted pathways might provide insights in the potential novel treatment targets for CAV.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council Advanced Researcher Grant and Proof-of-Concept Grant ROC curves of the urinary proteomicThe 25 highlighted enrichment pathways
The urinary proteomic profile of arterial stiffness in the general population
Authors: Wei D M , Melgarejo J , Thijs L , Ciarka A , Vanassche T , Van Aelst L , Janssens S , Mischak H , Staessen J A , Verhamme P , Zhang Z Y 
Published: October 2021

Abstract

Background
Although arterial stiffness is an independent predictor of cardiovascular outcomes, its physiopathology remains unclear.

Purpose
This study aimed to investigate the urinary proteomic profile of aortic stiffness and provide insights into pathogenetic processes of arterial stiffness by pathway analysis.

Methods
In 669 participants (mean age, 50.5 years; 48.9% men) randomly recruited from the Flemish population, we measured carotid-femoral pulse wave velocity (PWV) by applanation tonometry. The proteomics of urine samples was quantified by using capillary electrophoresis coupled mass spectrometry. The proteomic data were analysed by the orthogonal projections to latent structures, a supervised dimensional reduction statistic method and summarised as a urinary proteomic (UP) score.

Results
The mean values were 7.56±2.02 m/s for PWV and 7.59±1.95 unit for the UP score. PWV was significantly associated with the UP score before and after adjustment for the potential covariates (β coefficient: 0.81 and 0.75, respectively; p&lt;0.001). The significant proteins in the urinary proteomic profile consisted of 43 kinds of proteins, including collagen I, II and III, fibrinogen, matrix Gla-protein, apolipoprotein A-I and A-VI. The pathways annotated by the significant proteins mainly involved in fibrosis, signal conduction, platelet activation and aggregation.

Conclusions
In conclusion, the urinary proteomic profile could be a new biomarker of aortic stiffness and the altered proteins may link to the underlying mechanisms and holds the potential to discover novel therapeutic targets for arterial stiffness.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): The Internal Funds KU Leuven (STG-18-00379) Distribution and CorrelationThe Enrichment Pathways
Improvement of outcome prediction of hospitalized patients with COVID-19 by a dual marker strategy using high-sensitive cardiac troponin I and copeptin
Authors: Kaufmann C K , Ahmed A A , Kassem M K , Freynhofer M F , Jaeger B J , Aicher G A , Equiluz-Bruck S E , Spiel A S , Vafai-Tabrizi F V , Gschwantler M G , Fasching P F , Wojta J W , Giannitsis E G , Huber K H 
Published: October 2021

Abstract

Background
COVID-19 has been associated with a high prevalence of myocardial injury and increased cardiovascular morbidity. Copeptin, a marker of vasopressin release, has been previously established as a risk marker in both infectious and cardiovascular disease.

Purpose
Investigate the prognostic impact of copeptin and high-sensitive cardiac troponin I (hs-cTnI) in COVID-19.

Methods
This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from June 6th to November 26th, 2020 in a tertiary care hospital. Copeptin and hs-cTnI levels on admission were collected and tested for their association with the primary composite endpoint of ICU admission or 28-day mortality.

Results
A total of 213 eligible patients with COVID-19 were included of whom 55 (25.8%) reached the primary endpoint. Median levels of copeptin and hs-cTnI at admission were significantly higher in patients with an adverse outcome (Copeptin 29.6 pmol/L, [IQR, 16.2–77.8] vs 17.2 pmol/L [IQR, 7.4–41.0] and hs-cTnI 22.8 ng/L [IQR, 11.5–97.5] vs 10.2 ng/L [5.5–23.1], P&lt;0.001 respectively). ROC analysis demonstrated an optimal cut-off of 19.6 pmol/L for copeptin and 16.2 ng/L for hs-cTnI and an increase of either biomarker was significantly associated with the primary endpoint. The combination of raised hs-cTnI and copeptin yielded a superior prognostic value to individual measurement of biomarkers and was a strong prognostic marker upon multivariable logistic regression analysis (OR 4.274 [95% CI, 1.995–9.154], P&lt;0.001). Addition of copeptin and hs-cTnI to established risk models improved C-statistics and net reclassification indices.

Conclusion
The combination of raised copeptin and hs-cTnI upon admission is an independent predictor of deterioration (ICU admission) or 28-day mortality in hospitalized patients with COVID-19.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bürgermeisterfond der Stadt WienLudwig Boltzmann Cluster for Cardiovascular ResearchAssociation for the Promotion of Research on Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) Copeptin and hs-cTnI in COVID-19Biomarker based risk assessment
Pace of arterial aging and its association with cardiovascular risk factors
Authors: Akopyan A , Strazhesko I , Orlova I 
Published: October 2021

Abstract

Introduction
Chronological age is a well-known risk factor of cardiovascular diseases (CVD). In comparison with chronological age, biological arterial age can determine person's individual pace of aging, while difference between biological and chronological arterial age (delta age) can be rated as accelerated or decelerated artery aging.

Purpose
The aim of this study was to assess the association of risk factors of CVD with accelerated and decelerated arterial aging in almost healthy people.

Methods
We investigated systolic blood pressure (SBP), blood chemistry (total cholesterol (TC), low- (LDL) and high-density (HDL) lipoproteins, triglycerides (TG), apolipoprotein B (ApoB), fasting glucose (FG), glycated hemoglobin (HbA1c), serum renin levels) and urinary albumine, carotid ultrasonography (presence of atherosclerotic plaques and carotid intima-media thickness), arterial stiffness (AS) and leucocyte telomere length (LTL) in 143 adults (mean age 50.31±12.98 years, 35% male, 29% have hypertension, 15% - type 2 diabetes mellitus (T2DM)). LTL was measured by real-time polymerase chain reaction. AS was measured by pulse wave velocity and augmentation index with applanation tonometry using SphygmoCor device (AtCor, Australia). Biological artery age was estimated according to the age-predicting models, based on arterial wall parameters (A. Fedintsev et al, 2017). All the subjects were divided into groups of “old” and “young” arteries according to the positive or negative delta age – difference between biological and chronological age. The data were analyzed using multivariate logistic and linear regression analysis.

Results
The main statistically significant results are shown in the table.
Arterial pace of aging is closely associated with chronological age, hypertension and glucose metabolism. There were not found any associations of arterial pace of aging with lipid, renin levels, urinary albumin and LTL.

Conclusion
Hypertension, carbohydrate metabolism are main therapeutic targets for accelerated arterial aging and CVD prevention.

Funding Acknowledgement
Type of funding sources: None. Results of regression analysis
Role of S100A4 in atherosclerosis development
Authors: Cardoso Dos Santos L M , Ambartsumian N , Grigorian M , Bochaton-Piallat M L 
Published: October 2021

Abstract

Background
Smooth muscle cells (SMCs) accumulate into the intima during the process of atherosclerosis, where they switch from a contractile to a synthetic phenotype. We previously identified S100A4 as being a marker of the synthetic SMCs. Recently we have shown that extracellular S100A4 induces a pro-inflammatory-like SMC phenotype and is causally related to atherosclerotic plaque progression.

Aim
To study the role of intracellular S100A4 depletion in the SMC phenotypic transition during atherosclerosis.

Methods
We used a full S100A4 knockout (KO) mouse model, where we performed left common carotid ligation and collected carotid arteries after 4 weeks. Primary SMCs were cultured from wild type (WT) and KO animals. We investigated differentiation marker expression, NFκB activation with extracellular S100A4, proliferation and migratory capacities. Results are given as mean ± SD (Fig. 1A and B).

Results
In vivo, no difference in intimal thickening (IT) size and SMC differentiation marker expression was observed between WT and S100A4 KO mice. CD68 was absent and S100A4 was only detected in WT animals in the inner layer of the IT. In vitro, no difference in differentiation marker expression, proliferation (Fig. 1A) or NFκB activation (Fig. 1C) was observed. Interestingly, migration was decreased in the absence of S100A4 (Fig. 1B)

Conclusion
The in vivo abrogation of S100A4 does not interfere with IT progression, suggesting that the lack of inflammation in this model might render S100A4 expression neglectable and disguise a possible effect of S100A4 depletion in IT progression. In vitro, S100A4 plays a role in SMC migration.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation Figure 1
No direct involvement of Phactr-1 in non-atherosclerotic arteriopathies: results from 3 different Phactr-1 transgenic knockout mice
Authors: Rubin S , Bougaran P , Martin S , Abelanet A , Delobel V , Jeanningros S , Bats M L , Dufourcq P , Couffinhal T , Duplaa C 
Published: October 2021

Abstract

Introduction
Genome-wide association studies have revealed robust associations of common genetic polymorphisms in the Phactr1 locus (6p24) (encoding Phosphatase and Actin Regulator 1) with cervico-cerebral artery dissection (CCeAD), spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). These common elements of genetic predisposition provide a proof of concept for important shared mechanisms at the molecular level between CCeAD, SCAD and FMD vascular diseases.

Objective
Deciphering genetic, molecular and physiological importance of PHACTR1.

Method
Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells (EC) using 2 tissue-specific Cre-driver (one of them was embryonic) and Smooth Muscle Cells (SMC) with a third tissue-specific Cre-driver to assess its role in the pathogenesis of CCeAD, SCAD or FMD.

Results
To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed firstly, a decrease in Phactr1 transcription and Phactr1 expression in EC and SMC isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology or actin organization were not different in KO mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin-II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there was no more consequences of Phactr1 deletion during embryogenesis in ECs.

Conclusion
Loss of function of PHACTR-1 in the cell types mostly involved in vascular physiology does not appear to induce a pathological vascular phenotype.

Funding Acknowledgement
Type of funding sources: None.
Long-term post-discharge coagulation abnormalities in patients with moderate to severe COVID-19
Authors: Artemyeva G , Kalinskaya A , Dukhin O , Lebedeva A , Rozin A , Shpektor A , Vasilieva E 
Published: October 2021

Abstract

Introduction
Coagulopathy plays a significant role in COVID-19 pathogenesis. Benefit from anticoagulation is well established in hospitalized patients. But since there is a lack of data on coagulopathy resolution: there is no consensus in guidelines if extended anticoagulation is required.

Purpose
The purpose of our work was to analyze coagulation abnormalities at 2 to 5 months after moderate to severe COVID-19.

Methods
COVID-19 reconvalescents (CR), discharged from our hospital, were called for follow-up at 2–3 (CR1 group, 21 patients) or 5–6 (CR2 group, 26 patients) months after discharge. All CR were not on the anticoagulation therapy by that time. In addition to clinical examination and standard lab tests, we performed an FMD-test to analyze endothelial function, impedance aggregometry to analyze platelet aggregation, and a thrombodynamics test to assess thrombogenesis and fibrinolysis. The control group was recruited before the pandemic started.

Results
All CR were free from thrombotic complications after discharge from the hospital.
Endothelial function was not significantly impaired in CR compared with control, and was still in the normal range (7,07, IQR (3,36; 11,56) vs. 7,87 (5,42; 13,45)).
Platelet aggregation was significantly lower in CR1 than in the control group in ADP-induced mode (37, IQR (19; 47) vs. 46, IQR (41; 50), p=0,02) and didn't differ in other groups and other modes (Asa, TRAP-induced).
Thrombodynamics tests revealed suppression of the clot formation process in both CR1 and CR2 compared with control. There were decreased clot growth rates (μm/min) (CR1/CR2: 27,1, IQR (26,1; 29,2)/27,6, IQR (26,4; 30,0) vs. 32,2, IQR (30,0; 35,1), both p&lt;0,001); decreased clot size (μm) (CR1/CR2: 1099, IQR (1069; 1194)/1199, IQR (1058; 1221) vs. 1304, IQR (1164; 1380), both p&lt;0,001), and decreased optical density (arb units) (CR1/CR2: 21'607, IQR (20'363; 24'545)/22'741, IQR (21'344; 25'961) vs. 26'556, IQR (24'672; 29'387, p&lt;0,001 and p=0,09 respectively.
Fibrinolysis was enhanced in CR groups compared with control (lysis progression was significantly higher for CR2 only, CR1/CR2: 2,9, IQR (2,5; 3,8)/3,8, IQR (2,6; 5,4) vs. 2,5, IQR (1,1; 3,4) %/min, p=0,087 and p=0,007 respectively; expected clot lysis time was shorter in both CR1 and CR2: 36,5, IQR (29,8; 44,2)/31,7, IQR (24,3; 42,7) vs. 65,9. IQR (36,3; 95,5) min, p=0,019 and p=0,016 respectively).
There was no statistical difference in clot formation and in fibrinolysis between CR1 and CR2.

Conclusion
In the deferred period (2–5 months) of COVID-19 the fibrinolysis process remains still active whereas the process of clot formation is mostly suppressed. Endothelial function assessed via the FMD test is within the normal range in the post COVID period.

Funding Acknowledgement
Type of funding sources: None.
Is endothelial dysfunction a driving force of COVID-19 induced coagulopathy?
Authors: Dukhin O , Kalinskaya A , Molodtsov I , Maltseva A , Sokorev D , Elizarova A , Glebova K , Stonogina D , Shakhidzhanov S , Spiridonov I , Ataullakhanov F , Margolis L , Shpektor A , Vasilieva E 
Published: October 2021

Abstract

Background/Introduction
There are numerous reports regarding the direct endothelial damage by the SARS-CoV-2 that can lead to activation of both plasma hemostasis and platelet aggregation. However, the mechanism of interaction between endothelium and haemostasis in COVID-19 remains unclear.

Purpose
The aim of our study was to assess the relationship between each link of clot formation process (endothelial function, plasma coagulation, platelet aggregation) with the severity of the disease.

Methods
58 COVID-19 patients were included in our study. Patients were divided into moderate (n=39) and severe (n=18) subgroups. All patients underwent a flow-mediated dilation (FMD) test, impedance aggregation, rotational thromboelastometry, thrombodynamics and von Willebrand factor antigen (vWF: Ag) quantification. All measurements were repeated on days 3 (point 2) and 9 (point 3) of hospitalization.

Results
COVID-19 patients demonstrated the enhanced plasma coagulation (clotting time, s 613,0 [480; 820], clot growth rate, μm/min 32,75 [29,3; 38,7]). At point 1 no significant difference in parameters of plasma coagulation between patients' subgroups was noted. At point 2 a significant decrease in the size (CS, μm 1278.0 [1216.5; 1356.5] vs 965.0 [659.8; 1098.0], p&lt;0,01) and clot growth rate (μm/min 32,4 [29,2; 35,0] vs 17,7 [10,3; 24,4], p&lt;0,01) under the influence of anticoagulants in the moderate subgroup compared with point 1 was observed. We didn't observe such phenomenon in severe subgroup.
There was no significant difference in platelet aggregation between subgroups at point 1. During the course of the disease the patients in the moderate and severe subgroups demonstrated a significant increase in platelet aggregation induced by arachidonic acid and ADP (severe: AUC ARA 48,0 [25,0; 59,0] vs 77,5 [55,8; 92,7], p=0,04; AUC ADP 44,0 [41,0; 56,0] vs 58,0 [45,5; 69,0], p=0,04; moderate: AUC ARA 31,5 [19,8; 50,7] vs 56,0 [39,0; 76,0], p=0,01; AUC ADP 43,0 [20,0; 59,0] vs 56,6 [50,3; 70,5], p=0,04;), in moderate subgroup the significant increase in TRAP-induced aggregation was also noted (AUC TRAP 58,0 [41,0; 69,5] vs 76,0 [58,3; 81,5], p=0,048).
There were no significant differences in the FMD-test results between the patient subgroups. FMD-test results were predominantly within the reference ranges (7,1 [4,0; 8,8]).
Patients in the severe subgroup had significantly higher levels of vWF: Ag (228,0 [205,3; 240,7] vs 232,0 [226,0; 423,0], p=0,03).

Conclusion
SARS-CoV-2 infection was characterized by increased levels of vWF:Ag, that could represent the local endothelial damage, meanwhile there was no generalized endothelial dysfunction assessed via FMD-test in moderate to severe patients. At the same time the enhanced plasma coagulation in COVID-19 patients was observed.

Funding Acknowledgement
Type of funding sources: None.