bluuebunny/crossref_metadata_2025_split huggingface dataset:
ENHANCING INTERACTIONS BETWEEN MASR AND ETBR AS A NEW VASOPROTECTIVE STRATEGY
Authors: Kuriakose Jithin , Montezano Augusto C , Hood Katie Y , Alves-Lopes Rheure , Sin Angie Yy , Passaglia Patricia , Finaly Jane E , Basheer Sehrish , Yusuf Hiba , Hepburn Ross , Santos Robson A , Maclean Margaret R , Baillie George S , Touyz Rhian M 
Published: April 2021

Objective:
We demonstrated that the MAS and ETB receptors physically interact and may be involved in the protective actions of Ang(1–7) in endothelial cells (ECs). We assessed the biological role of MAS/ETBR interaction in the vasculature, focusing on the NO pathway.

Design and method:
Human ECs were stimulated with Ang(1–7) (10-7 M) in the presence/absence of A779 (MAS antagonist, 10-5 M), BQ788 (ETBR antagonist, 10-5 M) and MAS/ETBR peptide disruptor (10-5 M). ETBR expression and AKT/eNOS activation were evaluated by immunoblotting and NO production by DAF-FM fluorescence.

Results:
Ang(1–7) increased ETBR expression (50%), an effect blocked by A779 (p < 0.05 vs control). Ang(1–7) also induced AKT (40%) and eNOS (35%) activation; followed by an increase in NO production (2 fold) (p < 0.05 vs control). These effects were inhibited by A779, BQ788 and the MAS/ETBR disruptor. In a high throughput screening of a 20K protein:protein interaction modulator library, we discovered 23 potential enhancers of the MAS/ETBR interaction, where we tested 4 in ECs (Enh1–4: 10–5 M). All four MAS/ETBR enhancers increased eNOS activation with variable responses (Enh1: 44.2%; Enh2: 65.4%; Enh3: 80.7%; Enh4: 94.9% vs control, p < 0.05), but only treatment with Enh1 and Enh2 increased NO production (Enh1: 109.4%; Enh2: 46.5% vs control, p < 0.05) in ECs. Mesenteric resistance arteries were pre-incubated with Enh1–4 for 30 minutes prior to acetylcholine (Ach) curves, to assess endothelium-dependent relaxation. Enh1 decreased ACh-induced relaxation (Emax: 52.8 ± 2.9 vs Emax control: 70.4 ± 3.3), while Enh4 increased ACh-induced relaxation (Emax: 96.7 ± 4.6 vs Emax control: 70.4 ± 3.3), p < 0.05.

Conclusions:
Promoting the MAS/ETBR interaction with specific enhancers leads to eNOS activation and vasorelaxation, where Enh1–4 have variable effects. Current studies are focusing on identifying the most sensitive enhancer that will provide vasoprotection, and potentially new strategies in the treatment of vascular disease.
PARACHUTING - BUNGEE - MENTAL STRAIN WITH DISSIMILAR CARDIAC AND METABOLIC IMPACT
Authors: Kisters Klaus , Moser M. , Opresnik S. , Seibert F. , Porta S. 
Published: April 2021

Objective:
Parachuting and bungee jumping result in heavy mental strain with dissimilar cardiac and metabolic impact. In addition changes in blood pressure values and electrolyte metabolism may occur.
Therefore it was of interest to study blood pressure and ionized magnesium values as stress markers.

Design and method:
Out of 100 microlitres of capillary blood from 23 parachuters and of 15 bungee jumpers sampled before and after the jump, blood glucose and ionized magnesium concentrations were determined by a NOVA Phox-M device, distributed by TECOM, Austria. Blood pressure values were measured by Beurer Instrumentation, Ulm, Germany.

Results:
1. Parachuting:
Sytolic and diastolic blood pressure values increased significantly after the jump (p < 0.01).
Heart rate did not change significantly.
Blood glucose and ionized magnesium values decreased significantly from initially high normal values (p < 0.01).
2. Bungee jumping:
Also no difference in heart rate, but a slight fall in systolic and a significant fall in diastolic blood pressure values after the jump were noted (p < 0.01).
Blood glucose increased from already high basal levels and ionized magnesium values decreased significantly (p < 0.01).

Conclusions:
Outright stress determines the sympathoadrenal anticipation, epinephrine challenge should be not dissimilarly high. However, a longer anxiety period during the para-jump proceedings could lead to time dependent contrary reactions in blood pressure, magnesium and glucose levels, all of them stress markers of different sensibility.
Taken together:
ANGIOTENSIN II INDUCED SALT-SENSITIVE HYPERTENSION ASSOCIATED WITH INVERSE CIRCADIAN PATTERN IN RENAL GENERATION OF TUMOR NECROSIS FACTOR ALPHA AND ANGIOTENSINOGEN IN MICE
Authors: Majid Dewan S A , Navar L. Gabriel , Castillo Alexander , Khan Nadia , Shindler Isabella 
Published: April 2021

Objective:
Blood pressure (BP) in humans normally follows a circadian dipping pattern with a decline from day (active) to a night (inactive) period. Such dipping pattern is altered to a non-dipping pattern in salt-sensitive hypertension (SSH), the pathophysiological mechanism of which is not yet clearly understood. Angiotensin II (AngII) induced SSH associated with increased intrarenal AGT generation, which can be suppressed by tumor necrosis factor-alpha (TNFa) formation. We examined the hypothesis that AngII-induced TNF and AGT generation follows an inverse circadian pattern with a decrease in TNF during inactive period that facilitates increased AGT generation leads to non-dipping pattern in SSH.

Design and method:
Experiments were performed in mice (C57BL6 strain) chronically treated with or without AngII (25 ng/min; osmotic mini-pump) and high salt (HS; 4% NaCl) containing diets for 4 weeks. BP was measured at day and night periods by tail-cuff method. Circadian rhythm in urinary parameters in these nocturnal animals was assessed by 12 hour urine collections using metabolic cages during the active period (7PM to 7AM) and the inactive period (7 AM to 7 PM).

Results:
In untreated rats (n = 6), mean BP showed dipping pattern (90 ± 3 to 78 ± 2 mmHg from active to inactive period) AngII + HS treatment (n = 6) induced a non-dipping pattern of SSH (109 ± 2 to 106 ± 3 mmHg from active to inactive period). In untreated mice, urinary excretion of TNFa (uTNFa) was higher (0.5 ± 0.2 vs 0.13 ± 0.08 pg/hour) but urinary excretion of AGT (uAGT) was lower (0.28 ± 0.18 vs 0.46 ± 0.14 ng/hour) during the active period compared to that during the inactive period. This inverse relationship between uTNFa and uAGT was exaggerated in AngII+HS treated mice. There were marked increases in uTNFa during active periods (44.6 ± 14.6 pg/hour) which were less during inactive periods (12.1 ± 4.7 pg/hour). Interestingly, uAGT increment was lower during active periods (1.42 ± 0.97 ng/hour) than that in inactive periods (3.98 ± 1.67 ng/hour).

Conclusions:
TNFa generation suppresses intra-renal AGT formation during active periods but this phenomenon is inversed during inactive periods. The increase in AGT during the inactive period may facilitates a non-dipping BP pattern in SSH.
THE IMPACT OF ANTIHYPERTENSIVE DRUGS ON VASCULAR RIGIDITY AND ON THE GRADIENTS OF ARTERIAL STIFFNESS: A PILOT STUDY
Authors: Garneau Charles-Antoine , Fortier Catherine , Duval Karine , Agharazii Mohsen 
Published: April 2021

Objective:
Damages to barosensitive organs would be induced by the reversal of the arterial stiffness gradient. Our team has demonstrated that administration of nitroglycerin reduces regional stiffness of muscle arteries (radial and femoral) without modifying aortic stiffness, resulting in increased aortic-brachial (AB-PWV) and aortic-femoral (AF-PWV) stiffness gradients. The aim of this project is to study the impact of antihypertensive treatment on arterial stiffness, particularly on stiffness gradients.

Design and method:
This pilot study was performed in 19 hypertensive patients (age: 71 ± 11 years, men: 85%). The aortic, brachial and femoral stiffnesses were respectively measured by the carotid-femoral (cf-PWV), carotid-radial (cr-PWV) and femoral-dorsalis pedis (fd-PWV) pulse wave velocity during 2 visits: with and without medication for high blood pressure. During the drug-free visit, patients were to stop taking their antihypertensive drugs 2-3 days before their assessment, depending on their condition. The AB-PWV and AF-PWV ratios were obtained by dividing cf-PWV by cr-PWV or fd-PWV respectively.

Results:
At the visit without antihypertensive drugs, the cf-PWV, cr-PWV and fd-PWV were respectively 12.91 ± 0.65 m/s, 9.6 ± 0.4 m/s and 10.3 ± 0.3 m/s, resulting in an AB- ratio PWV of 1.37 ± 0.09 and an AF-PWV ratio of 1.21 ± 0.07. At the visit with medication, a significant decrease in mean arterial pressure of 9.5 mmHg (p < 0.001) was observed. In addition, reductions in cr-PWV of 0.79 m/s (p = 0.034) and fd-PWV of 0.45 m/s (p = 0.29) were noted, with no statistically significant change in cf-PWV (p = 0.83), leading to a non-significant increase in the AB-PWV (p = 0.21) and AF-PWV (p = 0.52) ratios.

Conclusions:
The preliminary data from this pilot project, although statistically non-significant, evolves in the same direction as those obtained with the administration of nitroglycerin. Indeed, there is a decrease in brachial and femoral stiffness leading to an increase in the gradients, which could have consequences for the microcirculation. These results suggest an impact of antihypertensive drugs on peripheral arteries and the vascular stiffness gradients, which could be confirmed with the continuation of this project on a larger sample.
A NOVEL URINARY BIOMARKER PREDICTS 1 YEAR MORTALITY AFTER DISCHARGE FROM INTENSIVE CARE
Authors: Zhang Zhen-Yu , Nkuipou-Kenfack Esther , Latosinska Agnieszka , Yang Wen-Yi , Fournier Marie-Céline , Blet Alice , Mujaj Blerim , Thijs Lutgarde , Feliot Elodie , Gayat Etienne , Mischak Harald , Staessen Jan , Mebazaa Alexandre 
Published: April 2021

Objective:
The urinary proteome reflects molecular drivers of disease. The aim of this study was to construct a urinary proteomic biomarker predicting 1 year post ICU mortality.

Design and method:
In 1243 patients, the urinary proteome was measured on ICU admission, using capillary electrophoresis couple with mass spectrometry along with clinical variables, circulating biomarkers (BNP, hsTnT, active ADM, and NGAL) and urinary albumin. Methods included support vector modelling to construct the classifier, Cox regression, the integrated discrimination (IDI) and net reclassification (NRI) improvement and area under the curve (AUC) to assess predictive accuracy, and Proteasix and protein-proteome interactome analyses.

Results:
In the discovery (deaths/survivors, 70/299) and test (175/699) datasets, the new classifier ACM128, mainly consisting of collagen fragments, yielding AUCs of 0.755 (95% CI, 0.708–0.798) and 0.688 (0.656–0.719), respectively. While accounting for study site, clinical risk factors, hazard ratios in 1243 patients were 2.41 (2.00–2.91) for ACM128 (+1 SD), 1.24 (1.16–1.32) for the Charlson Comorbidity Index (+1 point), and > = 1.19 (P < = 0.022) for other biomarkers (+1 SD). ACM128 improved (P < = 0.0001) IDI (>= + 0.50), NRI (>= + 53.7) and AUC (>= + 0.037) over and beyond clinical risk indicators and other biomarkers. Interactome mapping, using parental proteins derived from sequenced peptides included in ACM128 and in-silico predicted proteases, including/excluding urinary collagen fragments (63/35 peptides), revealed as top molecular pathways protein digestion and absorption, lysosomal activity and apoptosis.

Conclusions:
The urinary proteomic classifier ACM128 predicts the 1-year post ICU mortality over and beyond clinical risk factors and other biomarkers and revealed molecular pathways potentially contributing to a fatal outcome.
VON HIPPEL-LINDAU SYNDROME PRESENTING AS PHEOCHROMOCYTOMA COMPLICATED WITH MYOCARDIAL INFARCTION: A CASE REPORT
Authors: Yu Huizhen , Lin Lichao , Yu Peng , Chen Qing , Deng Chaochao 
Published: April 2021

Objective:
Von Hippel-Lindau syndrome (VHL), a rarely inherited disease with autosomal-dominant transmission, can be characterized by pheochromocytoma complicated with various clinical manifestations, such as paroxysmal hypertension, myocardial infarction, arrhythmia, and heart failure. The related case reports are rare, especially referring to myocardial infarction. However, it is important to obtain such a clinical case, since it may facilitate diagnose by utilization of genetic testing and prognosis by early surgical treatment.

Design and method:
A 53-year-old male patient presented with recurrent and progressive chest pain, hypertension, sweating and palpitation, associated with significant 15-year history of hypertension. Although these symptoms persisted 8 months, he did not receive any treatment before first hospitalization. Transthoracic echocardiography revealed left ventricular enlargement, left ventricular wall thickening, and the decrease of ejection fraction. Blood tests showed significant troponin I, catecholamine, and 24 hours urinary vanilla mantellic acid. ECG showed sinus tachycardia with ischemic changes. Besides, abdominal computed tomography scan revealed a tumor of 5.3 cm in diameter in the right adrenal gland. Thus, the patient was required to remove the tumor after 6 months. However, he hospitalized again due to those deteriorating symptoms. Coronary angiography revealed the left anterior descending stenosis 70%. Then he was admitted to intensive care unit and died of cardiogenic shock.

Results:
A diagnosis of this VHL syndrome was finally confirmed by genetic pedigree of the family and genetic testing. Gene tests showed that the patient and his daughter carried VHL gene c.G250C heterozygous missense mutation (VHL: p.V84L het), but the elder son without mutation in the same site. VHL type 2C, a subtype of VHL, is characterized by presenting as pheochromocytoma complicated with myocardial damage, myocardial infarction and heart failure.

Conclusions:
Test of the VHL gene mutation is necessary for the patients presenting as pheochromocytoma with myocardial infarction and their asymptomatic family members. Moreover, early surgical excision of pheochromocytoma may improve the prognosis of this disease.
AQUAPORIN-3 AND CYBA GENETIC POLYMORPHISMS MAY PREDICT RISK OF DEVELOPING HYPERTENSION
Authors: Da Silva Ines Margarida Vieira , Santos Ana Carolina , Matos Andreia , Da Silva Alda Pereira , Areias Maria Jose , Soveral Graça , Rebelo Irene , Bicho Manuel 
Published: April 2021

Objective:
Preeclampsia, a placentation disorder, affects 7% of pregnancies in Europe. It influences future cardiovascular disease, such as hypertension. Preeclampsia and hypertension have been associated with oxidative stress, therefore, key proteins in redox signaling may be involved with the development of hypertensive disorders during/after pregnancy. This study aimed at determining associations between oxidative stress-related gene polymorphisms (AQP3-rs2231231 and CYBA-rs4673) with the development of preeclampsia and the risk for future hypertension.

Design and method:
A cohort of 150pregnant Caucasian women, aged 35.24 ± 5.47 years, 60(40%) normotensive and 90(60%) preeclamptic, was evaluated. Based on a prospective study(2–16 years later), these women were evaluated for the development of hypertension and classified as normotensive 98(67%) or hypertensive 48(33%). The influence of genetic polymorphisms on the susceptibility for cardiovascular disease was evaluated. In this cohort, anthropometric/haemodynamic parameters were studied. For statistical analysis chi-square and Student t-test were used.

Results:
During pregnancy, no differences between the distribution of studied genetic polymorphisms in preeclampsia were found. However, based on the AQP3 dominant model of A, our data showed that AA+AC genotypes were more frequent (73.3%;p = 0.014) in hypertensive individuals. Moreover, allele A, the allele of risk, was associated with a 3.405-fold higher risk (p = 0.016,OR = 3.405,95%CI[1.26–9.19]) to develop hypertension after pregnancy. In addition, a higher systolic(p = 0.017) and diastolic(p = 0.008) pressure were also observed in women carrying the AA+AC genotype. Furthermore, based on CYBA dominant model of C, TT genotype of polymorphism was also correlated with the development of hypertension(100.0%;p = 0.007) after pregnancy. On the other hand, looking at the recessive model of C, CT+TT genotype was associated with the development of hypertension. Allele T, the allele of risk, was associated with 6.5-fold risk (p = 0,024,OR = 6.500,95%CI[1.28–33.03] to develop hypertension. Moreover, CT+TT genotypes of CYBA genetic polymorphism were more associated with increased weight (p = 0.014), higher waist circumference(p = 0.010), hip(p = 0.008) and systolic(p < 0.001) and diastolic blood pressure(p < 0.001).

Conclusions:
In this study, AQP3 genetic polymorphism was found associated with the hypertensive disorders after pregnancy for the first time. In addition, CYBA was also associated with the development of essential hypertension. These results open new perspectives in the development of new approaches for cardiovascular disease prevention.
A MULTI-SITE ANALYSIS OF THE HUMAN GUT MICROBIOME AND METABOLITES IN ASSOCIATION WITH AMBULATORY BLOOD PRESSURE
Authors: Marques Francine , Tsyganov Kirill , Ribeiro Rosilene , Gill Paul , Nakai Michael , Carrington Melinda , Yiallourou Stephanie , Muir Jane , Head Geoffrey A. , Kaye David 
Published: April 2021

Objective:
High blood pressure (HBP) is a major risk factor for cardiovascular disease (CVD) and the prevalence of both is higher in regional versus metropolitan areas. The gut microbiome has emerged as important contributor to HBP, however, the relationship between BP and specific gut microbes and their metabolites is unclear. Here we aimed to determine if specific gut microbes and key metabolites such as short-chain fatty acids (SCFAs) were associated with 24 h BP whether geographic differences exist in Australia.

Design and method:
We recruited 70 subjects from the community in metropolitan (n = 40) and regional (n = 30) locations in Australia. White coat hypertension was present in 6% and masked hypertension in 19% of the cohort, and 34% were hypertensive. We assessed office and ambulatory BP, dietary intake via food frequency questionnaire, gut metabolites by gas-chromatography, and gut microbiome by 16S sequencing.

Results:
Mean(±SD) 24 h mean arterial pressure was 90.5 ± 10mmHg, systolic BP 122.8 ± 14.9mmHg, and diastolic 74 ± 8.4mmHg. There was a positive correlation between plasma short-chain fatty acid butyrate and 24 h systolic (r = 0.31, P = 0.01) and diastolic BP (r = 0.29, P = 0.02), confirmed by logistic regressions adjusted for age, sex and BMI (P = 0.001). Fifty seven genus were significantly correlated with diastolic BP (r = 0.38–0.41) after adjustment for multiple comparisons (FDR < 0.1). Inverse Simpson index, a marker of alpha diversity, was negatively correlated with 24 h mean arterial pressure (r = -0.24, P = 0.04), being driven particularly by 24 h diastolic BP and day BP. There were no differences in alpha or beta diversity between metropolitan and regional areas. Participants from metropolitan areas, however, had significantly lower levels of total SCFAs, acetate and butyrate (P < 0.05) without having any differences in fibre intake.

Conclusions:
This is the first study to analyse BP as a continuous variable, suggesting it is associated with a less diverse gut microbiome, higher levels of butyrate, and several genus of gut bacteria. Further studies will need to determine a causal relationship for these associations. We did not find a gut microbial difference between metropolitan and regional participants, but the latter had lower levels of SCFAs, which could help explain their predisposition to hypertension and cardiovascular disease.
COMMON VARIANTS OF THE NDUFS8 GENE DO NOT CONFER GENETIC SUSCEPTIBILITY TO HYPERTENSIVE LEFT VENTRICULAR HYPERTROPHY IN HAN CHINESE
Authors: Guo Hao , Yu Zi-Yang , Zhang Xing , Zhu Cheng-Zhen 
Published: April 2021

Objective:
Left ventricular hypertrophy (LVH) is the most common target organ damage in essential hypertension. The serious degree of LVH is not proportional to the history of hypertension and level of blood pressure. It is suggested that other factors than hypertension are involved in the process of cardiac remodeling in hypertensive patients. Mitochondria dysfunction plays a vital role in the pathophysiology of hypertensive cardiac hypertrophy. The NADH dehydrogenase Fe–S protein 8 (NDUFS8) is one of the highly conserved nuclear-encoded subunits existing in human mitochondrial complex I. Defects in this subunit have been associated with Leigh syndrome, which is a diverse spectrum of clinical manifestation such as hypertrophic cardiomyopathy, psychomotor impairment, difficulty feeding and respiratory abnormalities. The study aim is to investigate whether the encoding NDUFS8 gene has associated with essential hypertension and hypertensive LVH.

Design and method:
In total of 1604 subjects, were Chinese-Han from Yunnan province, including 985 patients with essential hypertension (470 males and 515 females) and 619 healthy controls(240 males and 379 females). Six NDUFS8 tagSNPs (rs3751084, rs999571, rs2075626, rs1104739, rs3133269 and rs11228127) were genotyped and major haplotypes consisting of these six SNPs were reconstructed for all subjects.

Results:
The common genetic variants of the NDUFS8 genes have not positive associated with essential hypertension and hypertensive LVH. Haplotype GGCCTA was nominally significant associated with essential hypertension (P = 0.046). Nevertheless, no significant association was detected between the haplotype and the essential hypertension after bonferrioni corrections. Intriguingly, one NDUFS8 tagSNP (rs3751084), which showed marginally significant associated with decrease serum magnesium level, the patients’ frequency of the G allele of rs3751084 was significantly higher than among the healthy controls(P = 4.69 × 10-6).

Conclusions:
Our study indicated that common genetic variants of the NDUFS8 gene are unlikely to be involved in essential hypertension and hypertensive LVH. Of note, we can probably consider the rs3751084 as a significant regulator to serum magnesium level. Further studies are essential to characterize the role of the rs3751084-G in Torsades de points arrhythmia with hypomagnesemia.