bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting BACE1 to restore functional angiogenesis in type 2 diabetes
Authors: Clavane E , Cubbon RM , Caolo V , Meakin PJ 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation
British Microcirculation and Vascular Biology Society

Background
β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease notorious for its contribution to amyloid plaque formation in the pathophysiology of Alzheimer’s disease (AD) [1]. Further research has suggested a role for BACE1 in vascular homeostasis [2,3] and has shown that it proteolytically cleaves various angiogenic signalling factors including VEGF receptor 1 (VEGFR1) [2], NOTCH ligands [4] and the insulin receptor [5]. Similar to AD, BACE1 activity is elevated in models of type 2 diabetes [5], suggesting a potential role for its contribution to aberrant vessel growth characteristic of diabetes-related complications.

Purpose
Type 2 diabetes dramatically increases an individual's risk of developing microvascular complications and consequent lower limb amputations [6]. Therefore, identifying novel roles for BACE1 in angiogenic dysregulation will aid progression of future biomedical interventions in this field.

Methods
Retinal staining and the fibrin gel angiogenesis assay were used to identify a role for BACE1 in vessel growth in vivo and in vitro, respectively. Endothelium of the developing retinal vasculature in BACE1-/- and wild type (WT) mice was stained with IsolectinB4-Alexa488 and imaged using confocal microscopy. Sprout formation was further analysed using the fibrin gel angiogenesis assay with human umbilical vein endothelial cells (HUVECs) treated with or without a highly specific BACE1 inhibitor or transfected to over-express BACE1. Primary isolated pulmonary endothelial cells (PECs) were isolated from BACE1-/- and wild type control mice prior to Western blots, and real-time PCR.

Results
BACE1-/- retinas had increased branch points, vasculature area and quantity of filopodia compared to WT mice. Moreover, BACE1-/- PECs had reduced NOTCH1 signalling (26.73% ± 14.15, P=0.05) and soluble Jagged-1 protein (28.48% ± 14.61, P=&lt;0.05). HUVECs treated with a BACE1 inhibitor had increased sprouting (18.70%± 5.92, P=&lt;0.05) as well as increased phosphorylation of eNOS (83% ± 22, P=&lt;0.05) and Akt (85.5% ± 9.24, P=NS) compared to untreated cells. Moreover, HUVECs transfected to over-express BACE1 had decreased sprouting (35.22% ± 7.34, P=&lt;0.01) and increased NOTCH1 signalling (23.4% ± 2.42, P=0.01).

Conclusion
Our findings indicate a role of BACE1 in negatively regulating angiogenesis, possibly via NOTCH1 or Akt/eNOS/NO signalling. This provides a potential therapeutic purpose for BACE1 inhibitors, previously trialled to treat AD, in normalising BACE1 levels in individuals with type 2 diabetes and preventing associated microvascular complications.
Deleterious effect of serum from stemi patients on endothelial cell viability: implication on the resulting cardiac structure
Authors: Rios Navarro C , De Dios E , Gavara J , Perez-Sole N , Marcos-Garces V , Chorro FJ , Ruiz-Sauri A , Bodi V 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (grant numbers PI20/00637 and CIBERCV16/11/00486) and Conselleria de Educación – Generalitat Valenciana (PROMETEO/2021/008).

Aim
To evaluate the potential deleterious effect of serum from STEMI patients on cardiovascular magnetic resonance (CMR)-derived edema, hemorrhage and microvascular obstruction as well as on the grade of permeability in vitro by promoting endothelial cell apoptosis and necrosis in vitro.

Methods
Human coronary artery endothelial cells (HCAEC) were incubated with serum isolated 24h post-reperfusion from 43 STEMI patients submitted to CMR and from 10 control subjects. Using a multidisciplinary approach on HCAEC, the effect of serum from STEMI patients on the activation of apoptosis and necrosis as well as on changing the permeability and structure of the endothelial monolayer was assessed. The association between the serum-induced apoptosis and necrosis in vitro on HCAEC and CMR-derived edema, hemorrhage, and microvascular obstruction as well as the grade of permeability in vitro was also dissected.

Results
Serum from STEMI patients activated apoptosis (p&lt;0.01) and necrosis (p&lt;0.05) in HCAEC, evaluated by flow cytometry, enzymatic, genetic, and morphological analysis, and also provoked an increased in the permeability of the endothelial monolayer in vitro (p&lt;0.01), due to enlarged intercellular spaces (p&lt;0.05). Those patients whose serum induced higher necrosis in vitro displayed extensive CMR-derived edema (p&lt;0.01), hemorrhage (p&lt;0.01), and microvascular obstruction (p&lt;0.05) as well as more endothelial permeability in vitro (p&lt;0.05).

Conclusions
By activating apoptosis and necrosis on endothelial cells, serum from STEMI patients participates in the appearance of edema, hemorrhage, and microvascular obstruction as well as in increasing endothelium permeability. The negative effect of serum on the endothelial barrier can contribute to the adverse cardiac structure post-STEMI.
Complement C5 plasma levels are associated to abdominal aortic aneurysm prevalence and progression
Authors: Martinez-Lopez D , Mendez-Barbero N , Roldan-Montero R , Cerro-Pardo I , Picatoste B , Ortega-Villanueva L , Rodriguez De Cordoba S , Blanco-Colio LM , Linhdolt JS , Martin-Ventura JL 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Complemento II-CM
La Caixa

Aim
Previous human and experimental studies have suggested a role of complement activation in abdominal aortic aneurysm (AAA). We recently described an increase in complement C5 levels in plasma of subjects with subclinical atherosclerosis (1). Our aim was to investigate the potential association of C5 with AAA presence and progression.

Material and methods
Tissue and tissue-conditioned media from AAA (thrombus and wall) or healthy samples were obtained from surgical repair or brain-deceased organ donors, respectively. Blood samples from 490 AAA patients (maximal aortic diameter ≥30 mm) were obtained within a population-based ultrasound-screening trial in Danish men and from 176 age-matched screened negative controls. C5 protein levels were assessed by immunohistochemistry and ELISA.

Results
High C5 positive immunostaining was observed in AAA thrombus and media, while the staining in healthy arteries was faint. C5 levels were higher in tissue-conditioned media from AAA thrombus and AAA media as compared to healthy arteries (7.1±1 vs 2.9 ±0.5 vs 1.2±0.2ug/ml, p&lt;0.0001 for both). C5 plasma levels in AAA patients were higher than in controls (116±8 vs 61±7 ug/ml, P&lt;0.001). AAA patients at the upper tertile of C5 at baseline had a 25% higher risk of needing surgical repair during the follow-up (Hazard Ratio=1.25, 95% confidence interval, 1.045;1.511, P&lt;0.05).

Conclusions
C5 is associated to AAA presence and progression suggesting its potential use as a prognostic marker. Future studies are needed to clarify the pathogenic role of C5 in AAA.
Identification of CD8+ T cell PRDM1 in high-risk human plaques and its regulatory role in murine lesion development
Authors: Maas SL , Jin H , Lu C , Nagenborg J , Manca M , Karel JMH , Cavill R , Waring O , Sikkink CJJM , Mees BME , Daemen MJAP , Smirnov E , Sluimer J , Van Der Vorst EPC , Biessen EAL 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fritz Thyssen Stiftung
T cells have a prominent role in the pathogenesis of atherosclerosis, although their function in atherosclerotic plaques is only partly understood. In this study, we utilize the advantages of high-throughput techniques and data analytic strategies to compare the inherent biological changes of T cells during plaque transition from a stable, non-haemorrhaged (low-risk) to a rupture-prone, haemorrhaged (high-risk) phenotype.
We classified 43 human carotid arterial lesions into high- and low-risk plaques based on the presence/absence of intraplaque hemorrhages. RNA from these lesions was isolated and microarray gene expression data was obtained and analyzed by Weighted Gene Co-expression Network Analysis. A strong T cell signalling signature was identified in high- versus low-risk plaques, influencing angiogenesis and interferon-related processes. Bayesian network inference, cell type deconvolution and single-cell RNA sequencing analysis revealed that the T cell-associated gene program was linked to effector-memory cytotoxic, CD8+ T cells. This gene program appeared driven by CD8+ T cell-related transcription factors, including RUNX3, IRF7 and most importantly PRDM1. To validate these findings, we demonstrated in a murine model that T cell PRDM1 plays a key role in plaque formation, as atherosclerotic mice with a T cell specific Prdm1 deficiency developed larger and more advanced atherosclerotic plaques compared to control mice.
In conclusion, our study unveils a clear PRDM1-regulated effector-memory cytotoxic CD8+ T cell footprint in plaque development and the shift from low- to high-risk plaques, thereby revealing CD8+ T cells and PRMD1 as potential targets for intervention in adverse T cell responses in human atherosclerotic lesions.
Oscillatory shear stress augments endothelial pannexin1 by inhibiting macro-autophagy
Authors: Molica F , Hautefort A , Idris T , Pelli G , Foglia B , Kwak BR 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Introduction
Atherosclerotic lesions preferentially develop in arterial regions exposed to disturbed blood flow, which are characterized by a dysfunctional proinflammatory endothelial cell (EC) phenotype. ECs release ATP in response to changes in wall shear stress (WSS), which subsequently regulates the inflammatory response. ATP can be released from cells in a controlled manner through Pannexin1 (Panx1) channels.

Objective
To study the expression of Panx1 in response to WSS and its role in the endothelium.

Methods
Human ECs (HUVECs or EA.hy926) were exposed to physiological high laminar shear stress (HLSS) and atheroprone oscillatory shear stress (OSS) for 48h using an orbital shaker. Panx1 transcript and protein levels were determined by qPCR and Western blot, respectively. mRNA was extracted for RNAseq. WSS-modifying casts were placed for 1 week around the carotid artery of mice and Panx1 expression was analyzed en face. Carotid WSS-modifying casts were also placed in Tie2CreTgPanx1fl/flApoE-/- and Panx1fl/flApoE-/- mice followed by 9 weeks high fat diet. CD68+ cells were quantified in OSS-induced atherosclerotic lesions.

Results
We found that Panx1 expression was increased in carotid regions exposed to OSS as compared to HLSS regions. These results were confirmed in vitro in HUVECs. In silico analysis of the promotor of Panx1 revealed binding sites for the WSS-sensitive transcription factors NF-kB and CREB. NF-kB and CREB mRNA levels were similar under OSS and HLSS, however NF-kB activation (phospho-NF-kB) was detected in ECs under OSS. Surprisingly, Panx1 mRNA level was not affected under these conditions, suggesting that the increased Panx1 protein observed under OSS may be due to decreased Panx1 degradation rather than to increased synthesis of the protein. Unbiased analysis of differential gene expression in ECs exposed to HLSS or OSS revealed 320 up-regulated and 353 down-regulated genes under OSS. Down-regulated genes included proteins involved in macro-autophagy. Inhibition of macro-autophagy in ECs by exposure to chloroquine for 6h increased the expression of glycosylated Panx1, suggestive for more Panx1 channels at the plasma membrane under these conditions. Finally, we observed that atherosclerotic lesions in OSS regions of Tie2CreTgPanx1fl/flApoE-/- mice contained more CD68+ cells than Panx1fl/flApoE-/- controls.

Conclusion
Endothelial Panx1 expression is upregulated in response to OSS. Absence of OSS effects on NF-kB, CREB and Panx1 mRNA revealed that the upregulation of Panx1 protein is not due to transcriptional effects of OSS. Expression of genes involved in the macro-autophagic process were down-regulated under OSS, and chemical inhibition of macro-autophagy augmented the plasma membranous form of Panx1. OSS-induced decrease in autophagic flux may enhance ATP release through Panx1 channels, thereby counterbalancing leukocyte recruitment in atherosclerosis.
Comparison of lung functions of normal and hypertensive individuals
Authors: Oza Patel F , Vyas HARITA , Tanna KRIMA 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Introduction
Hypertension is a medical condition in which the blood pressure is chronically elevated. It normally refers to arterial hypertension. In past years, the diastolic value was emphasized in assessing HTN. However elevation SBP is also associated with increased incidence of coronary and cardiovascular diseases (e.g. stroke). Therefore both SBP and DBP value are important to note.
Pulmonary function test measures the function of lung capacity and lung and chest wall mechanics to determine whether or not the patients have a lung problem. Lung functions tests are commonly referred as —PFTs||. When a patient is referred for PFTs, it means that a battery of tests may be carried out including: simple screening spirometry, static lung volume measurement, diffusing capacity of carbon monoxide, airway resistance, respiratory muscle strength and arterial blood gases. Forced vital capacity (FVC) is the maximum volume of air which can be exhales or inspired during forced maneuver. Forced expired volume in one second (FEV1) is the volume of air expired in the first second of maximal expiration after a full inspiration. The total volume of air that is exhaled during forced expiration is called FVC. It is the FEV1 expressed as percentage of FVC and give the clinically useful index of airflow limitation. The greatest flow rate achieved during forceful expiration are called Peak Expiratory Flow Rate (PEFR) and usually taken as an indicator of larger airway resistance.

Aim
To compare the lung functions of normotensive and hypertensive individuals.

Methodology
Study Design: Cross-sectional Study
Study Duration: Total study duration was 6 months.
Subjects: 30 subjects
Sampling Design: Purposive sampling
Procedure- Ethic's approval and written informed consent of the subjects was taken prior to study. Procedure and purpose of the study was explained to the participants. In this study male and female between age group of 35 to 65 years who were Non-smokers and willing to participate were included. Subjects who were Smokers or who had URTI, any cardio Respiratory Illness or Any major Neuromuscular or musculoskeletal disorders were excluded. Participants were divided into two groups: one who was having HTN and other who were normotensive.
Outcome measures:
FEV1 % of predicted
FVC% of predicted
PEFR% of predicted

Results
Statistical analysis was done by SPSS version 16.Mann-Whitney U test was applied to see difference of lung function in hypertensive and normotensive individuals. Pulmonary function test parameters in hypertensives were statistically significantly lesser than normal controls (p&lt;0.05).

Conclusion
Lung functions of hypertensive individuals shows significant reduction as compared to the normotensive individuals. Thus, it can be concluded that persistent high blood pressure is responsible for altered pulmonary functions.
Necroptosis, unlike pyroptosis mediates right ventricular damage in pulmonary arterial hypertension
Authors: Jarabicova I , Horvath C , Velasova E , Bies Pivackova L , Veteskova J , Klimas J , Krenek P , Adameova A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic
The Slovak Research and Development Agency

Introduction
Necroptosis has been found to underlie myocardial damage in various pathological states, however its role as well as its potential interconnection to another cell damaging processes under conditions of pulmonary arterial hypertension (PAH) remains insufficiently understood.

Purpose
In view of these facts, we aimed to investigate the signalling of both necroptosis and pyroptosis in the lung and right ventricular (RV) tissue affected by PAH and we also examined the circulating levels of receptor-interacting protein kinase 3 (RIP3).

Methods
Male Wistar rats were administrated either vehicle (Control group) or monocrotaline (MCT) (60 mg/kg, s. c.) to induce PAH. The MCT-treated animals were sacrificed 4 weeks after the treatment (MCT group) or prematurely, based on rapid health deterioration, thereby indicating the advanced stage of PAH (ptMCT group). Pulse oximetry, gravimetry and evaluation of myocardial damage markers were used to assess the development of PAH. The molecular analyses (ELISA, RT-qPCR and immunoblotting) were used to examine the potential underlying mechanisms of tissue damage due to cell death.

Results
In the RVs, the expression of both pThr231/Ser232-RIP3 and pSer345-mixed linkage kinase domain-like protein was elevated equally in both PAH stages, strongly indicating promotion of necroptosis. Contrary in the lungs affected by PAH, the upregulation of pThr231/Ser232-RIP3 likely proceeded to pyroptotic rather than necroptotic cell death activation, as evidenced by caspase-1 and N-terminal gasdermin D increase. Moreover, we found that the plasma RIP3 levels increased with the severity of PAH stage and positively correlated with RV hypertrophy, but not with cardiac hemodynamic stress markers.

Conclusions
In summary, we showed for the first time that PAH-induced damage of RV and lung tissue might be mediated by different necrosis-like cell death forms with a crucial role pThr231/Ser232-RIP3. Furthermore, we suggested that the plasma RIP3 might serve as an additional diagnostic and prognostic marker of cardiac damage due to PAH.
Evaluation of the quality of screening for hypertension
Authors: Bekbergenova ZH , Derbissalina G , Umbetzhanova A , Batarbekova SH , Masharipova A , Mauletbayeva G , Akhmetova D , Kelimberdiyeva E 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None. Main funding source(s): -

Background/Introduction
Hypertension is one of the most common causes of myocardial infarction and stroke in the Republic of Kazakhstan (RK). In RK, screening for hypertension is performed with 40-years of age.

Purpose
To assess the quality of the screening for hypertension.

Methods
A survey of 354 patients with hypertension identified at screening was carried out.

Results
The average age of patients is 54 years [Q1-Q3: 50-54], of which 36.2% are men, 63.8% are women. In 66.7% of patients, heredity is burdened. According to the analysis of medical records, 117 (33.1%) patients smoke, while polling the same patients, 175 (49.4%) people smoke, which is 16.3% higher. According to the analysis, 38 (10.7%) patients drink, when we interviewed the same patients, 62 (17.5%) people drink, which is 6.8% higher. According to the analysis, 219 (61.9%) patients perform daily physical activity, according to our data, 111 (31.4%) people, which is 30.5% lower.
Middle systolic blood pressure is 140 [Q1-Q3: 130-140] mm Hg. Most of the respondents have varying degrees of obesity. The average body mass index is 31.86 [Q1-Q3: 29.4-31.86]. The average waist is 95 [Q1-Q3: 92-95]. Mean values of total cholesterol. 5.8 [Q1-Q3: 5.6-5.8]. During the electrocardiographic study, changes were identified in 69 patients (32 women, 37 men).

Conclusion (s)
During the initial questionnaire survey and clinical examination of patients with arterial hypertension at screening in 2015 and comparison with retrospective data, it became clear that such risk factors as tobacco smoking, alcohol consumption and daily physical activity were unreliable. Unfortunately, our work also has limitations and may be subject to subjective error, for example, we were unable to establish contact with the patient and a trusting relationship with the patient, or memory errors.
Diurnal variation in thrombotic and fibrinolytic status in healthy volunteers
Authors: Gue Y , Memtsas V , Kanji R , Gorog D 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): East and North Hertfordshire NHS Trust

Background
Previous studies assessing markers of fibrinolysis in healthy volunteers and patients with coronary artery disease (CAD) indicate circadian variation, primarily attributable to changes in plasminogen activator inhibitor-1 (PAI-1) concentrations, the main inhibitor of fibrinolysis, peaking between midnight and 06:00 hrs, with a nadir at 01:00 hrs. Whether the elevated PAI-1 translates into a global impairment of fibrinolysis, is not known.

Purpose
It was our aim to assess diurnal variation in global fibrinolytic activity in healthy subjects.

Methods
A single centre, prospective, observational study was conducted in healthy volunteers. Blood samples were obtained at two different time points on the same day, with a minimum inter-sample interval of 8 hours and a maximum of 12 hours. Venous blood was assessed to determine global thrombotic and fibrinolytic status in native whole blood status using the automated, point-of-care Global Thrombosis Test (GTT). This utilises non-anticoagulated blood to assess the time taken to form an occlusive thrombus under high shear (occlusion time) and the time taken for spontaneous restart of flow as a measure of endogenous fibrinolysis (lysis time).

Results
A total of 25 healthy volunteers (36% male), aged 34±12 y were included. All were non-smokers with a BMI of 25 (22.3 – 27.5) kg/m². The median interval between samples was 8:05 [hh:mm] (IQR 8:30 – 9:10). Occlusion time was similar in the morning and evening samples (median 451s [389 – 590] vs. 524s [428 – 597], p=0.207). Lysis time was also similar between morning and evening (median 1792s [1622 -2097] vs. 1726s [IQR 1517 – 1891], p=0.265).

Conclusion
Compared to the known circadian variation of thrombotic and fibrinolytic activity attributable to PAI-1, global thrombotic and fibrinolytic status do not appear to exhibit diurnal variation. Further studies are needed to assess how this correlates to t-PA and PAI-1 levels and the status in patients with cardiovascular disease.