bluuebunny/crossref_metadata_2025 huggingface dataset:
RNase R is associated in a functional complex with the RhpA DEAD-box RNA helicase inHelicobacter pylori
Authors: Tejada-Arranz Alejandro , Matos Rute G , Quentin Yves , Bouilloux-Lafont Maxime , Galtier Eloïse , Briolat Valérie , Kornobis Etienne , Douché Thibaut , Matondo Mariette , Arraiano Cecilia M , Raynal Bertrand , De Reuse Hilde
Published: April 2021

Ribonucleases are central players in post-transcriptional regulation, a major level of gene expression regulation in all cells. Here, we characterized the 3′-5′ exoribonuclease RNase R from the bacterial pathogen Helicobacter pylori. The ‘prototypical’ Escherichia coli RNase R displays both exoribonuclease and helicase activities, but whether this latter RNA unwinding function is a general feature of bacterial RNase R had not been addressed. We observed that H. pylori HpRNase R protein does not carry the domains responsible for helicase activity and accordingly the purified protein is unable to degrade in vitro RNA molecules with secondary structures. The lack of RNase R helicase domains is widespread among the Campylobacterota, which include Helicobacter and Campylobacter genera, and this loss occurred gradually during their evolution. An in vivo interaction between HpRNase R and RhpA, the sole DEAD-box RNA helicase of H. pylori was discovered. Purified RhpA facilitates the degradation of double stranded RNA by HpRNase R, showing that this complex is functional. HpRNase R has a minor role in 5S rRNA maturation and few targets in H. pylori, all included in the RhpA regulon. We concluded that during evolution, HpRNase R has co-opted the RhpA helicase to compensate for its lack of helicase activity.
A systematic comparison of ionization temperatures between ionizing and recombining plasmas in supernova remnants
Authors: Yamauchi Shigeo , Nobukawa Masayoshi , Koyama Katsuji
Published: April 2021

The temperatures of the plasma in supernova remnants (SNRs) are initially very low just after the shock heating. The electron temperature (kTe) increases quickly by Coulomb interaction, and then the energetic electrons gradually ionize atoms to increase the ionization temperature (kTi). The observational fact is that most young and middle-to-old SNRs have lower kTi than kTe after the shock heating. The temperature evolution in shell-like SNRs has been explained by this ionizing plasma (IP) scenario. On the other hand, in the last decade, a significant fraction of mixed-morphology SNRs was found to exhibit a recombining plasma (RP) with higher kTi than kTe. The origin and the evolution mechanism of RP SNRs have been puzzling. To address this puzzle, this paper presents kTe and kTi profiles using follow-up Suzaku observations, and then proposes a new scenario for the temperature and morphology evolution in IP and RP SNRs.
Explaining Intergovernmental Coordination during the COVID-19 Pandemic: Responses in Australia, Canada, Germany, and Switzerland
Authors: Schnabel Johanna , Hegele Yvonne
Published: April 2021

The COVID-19 pandemic required prompt action from governments all over the world. In federal systems, it can be important or beneficial to coordinate crisis management between the various governments. The extent to which intergovernmental coordination occurred and the form it took (vertical or horizontal) varied across countries and regarding the measures taken. By examining the introduction and the subsequent easing of containment measures and the procurement of medical supplies in Australia, Canada, Germany, and Switzerland, this article identifies the circumstances under which intergovernmental coordination occurs. Surprisingly, the existence of strong intergovernmental councils did not lead to closer intergovernmental coordination. Governments coordinated more intensively when jurisdiction was shared, problem pressure was high, and measures were(re-)distributive in nature. Vertical coordination was more likely when vertical intergovernmental councils existed and powers were shared.
Occurrence, Characteristics, and PCR-Based Detection of Pectobacterium polaris Causing Soft Rot of Chinese Cabbage in China
Authors: Chen Changlong , Li Xiaoying , Bo Zijing , Du Wenxiao , Fu Lu , Tian Yu , Cui Shuang , Shi Yanxia , Xie Hua
Published: April 2021

Bacterial soft rot is an important disease of Chinese cabbage (Brassica rapa L. ssp. pekinensis) in China and many other countries. Four pectinolytic bacterial strains (WBC1, WBC6, WBC9, and WBC11) were isolated from soft-rotted Chinese cabbage in Beijing, China. Based on 16S rDNA and pmrA gene sequence analyses, multilocus sequence analysis (MLSA), and genomic average nucleotide identity (ANI) analysis, these four strains were identified as Pectobacterium polaris. This species, previously reported from potato in countries not including China, is a new soft rot pathogen of Chinese cabbage in China. Biochemical characteristics of these P. polaris strains tested by Biolog were mostly consistent with those of P. polaris NIBIO1006T. Their pathogenicity on Chinese cabbage is temperature dependent, with all four strains as well as the type strain exhibiting high pathogenicity at 23°C and 28°C. These four strains infected Lactuca sativa, Daucus carota, Solanum tuberosum, and Capsicum annuum by artificial inoculation. Specific polymerase chain reaction (PCR) and quantitative PCR (qPCR) primers for P. polaris were developed on the basis of its specific gene sequences (determined by genome comparison methods). Both PCR and qPCR detected not only genomic DNA of P. polaris but also the pathogen from diseased plant tissues even before external symptoms appeared. Their detection sensitivities were as low as 1 pg and 100 pg genomic DNA of P. polaris, respectively. To our knowledge, this study is the first to both report the emergence of P. polaris on Chinese cabbage in China and provide rapid and accurate PCR/qPCR-based detection systems specific for P. polaris.
PROTEOMIC ASSESSMENT OF CIRCULATING MICROPARTICLES IN HYPERTENSION AND DIABETES
Authors: Varol Ozgun , Turner Maddison , Thibodeau Jean-Francois , Holterman Chet , Kennedy Christopher , Burger Dylan
Published: April 2021

Objective:

It is estimated that 415 million individuals are living with diabetes and an estimated 1.13 billion individuals worldwide have hypertension. Hypertension and diabetes are both associated with increased cardiovascular risk however the molecular changes to the vasculature associated these conditions are not fully understood. In the present study we examined the protein composition of circulating microparticles (MPs) in hypertensive, diabetic and healthy mice to identify common and disease-specific molecular changes.

Design and method:

Protein content was assessed in microparticles isolated from platelet-poor plasma of transgenic mice expressing human renin in the liver (TtRhRen, hypertension model), OVE26 type 1 diabetic mice and wild-type (WT) FVBN mice. Microparticles were isolated by differential centrifugation and protein content was analyzed using liquid chromatography mass spectrometry (LC-MS/MS).

Results:

We identified a total of 297 independent proteins with at least 2 peptides per protein. Of these, 163 proteins were found in all groups studied, 48 were exclusive to WT mice, 23 were exclusive to OVE26 mice and 4 were exclusive to TtRhRen mice. In addition, 22 proteins were observed with > 1.5 fold change (FC) compared to wild-type mice, and 68 proteins were reduced by > 50%. Amongst the top ten differentially expressed proteins, fibrinogen was upregulated in both OVE26 and TtRhRen mice compared with wild-type controls. Similarly Trem-like transcript 1, sarcoplasmic/ endoplasmic reticulum calcium ATPase 3 and junction plakoglobin were all downregulated in both OVE26 mice and TtRhRen mice. Conversely, arginase was up-regulated in diabetic, but not hypertensive mice while carboxypeptidase was up-regulated in hypertensive but not diabetic mice. Gene ontology (GO) analysis of 96 proteins unique or enriched in MPs from OVE26 mice indicated the presence of proteins involved in arginine biosynthesis and blood coagulation. GO analysis of TtRhRen-enriched proteins indicated presence of proteins associated with integrin signaling and inflammation.

Conclusions:

In summary, assessment of MP protein composition revealed common and disease-specific changes in diabetes and hypertension. Further analysis of these changes may lead to the identification of novel pathways associated with the pathogenesis of vascular injury in hypertension and diabetes.
GENES ASSOCIATED WITH BLOOD PRESSURE TRAITS SHOW CELL TYPE-SPECIFIC EXPRESSION AND CONTROL MULTIPLE CAUSAL LINKS TO BLOOD PRESSURE REGULATION IN THE HUMAN KIDNEY
Authors: Eales James , Jiang Xiao , Xu Xiaoguang , Saluja Sushant , Cano-Gamez Eddie , Pramanik Sanjeev , Bogdanski Pawel , Wystrychowski Wojciech , Zywiec Joanna , Zukowska-Szczechowska Ewa , Woolf Adrian , Maffia Pasquale , Guzik Tomasz , Samani Nilesh , Charchar Fadi , Tomaszewski Maciej
Published: April 2021

Objective:

Hypertension affects 35% of the global adult population. It is a major risk factor for stroke, heart failure and coronary artery disease and is the leading preventable risk factor for premature death globally. Here we describe our approach to determine the causal pathways between genetic variants and blood pressure through the expression of kidney genes.

Design and method:

We used a catalogue of all known blood pressure associated genetic variants, gene expression profiles from 430 human kidney tissue samples and a single-cell gene expression data set to identify causal relationships with blood pressure using a colocalisation analysis and an ensemble of Mendelian randomisation methods.

Results:

By combining genome-wide genotypes and gene expression profiles from RNA-sequencing in an expression quantitative trait loci (eQTL) analysis we identify 418 genes where expression is modified by genetic variants previously associated with blood pressure traits. To investigate how these genes are expressed in the kidney we used gene expression profiles from 41,778 human renal cells and identified 390 (93%) of these genes to be expressed in these cells with 69 (18%) showing expression specific to individual renal cell types. There was a statistically significant enrichment for expression of blood pressure associated genes in juxtaglomerular cells and cells from the collecting tubule. We identified 111 genes where the eQTL and blood pressure association colocalised and then applied an ensemble of Mendelian randomisation (MR) methods to determine which genes also have a causal effect on blood pressure in the kidney. Our MR analysis identified 53 (13%) genes where expression is causally linked to blood pressure, these included: guanylate cyclase 1 (GUCY1A3), the main receptor for nitric oxide and the target of riociguat and nuclear receptor coactivator 7 (NCOA7) which regulates vacuolar proton pumping ATPase (V-ATPase) activity in the intercalated cells of the collecting duct.

Conclusions:

We have identified 53 kidney genes where expression is causally linked to blood pressure. This not only highlights the importance of the kidney in blood pressure regulation, but also identifies putative targets for drug development or repurposing.
LEFT VENTRICULAR MASS AND URINARY METABOLOMICS IN YOUNG BLACK AND WHITE ADULTS: THE AFRICAN-PREDICT STUDY
Authors: De Beer Dalene , Mels Catharina Mc , Schutte Aletta E. , Louw Roan , Delles Christian , Kruger Ruan
Published: April 2021

Objective:

Increased left ventricular mass is an independent predictor for cardiovascular events, and shown to be higher in black than white populations. To gain a better understanding of early factors contributing to increased left ventricular mass in young black adults, we investigated metabolomic profiles and identified metabolites associated with left ventricular mass index in healthy black and white adults aged 20–30 years.

Design and method:

We included normotensive black (N = 80) and white (N = 80) participants from the African-PREDICT study, with data on urinary metabolomics and echocardiography. Urinary metabolites were measured using nuclear magnetic resonance spectroscopy, liquid chromatography tandem mass spectrometry and gas chromatography time-of-flight mass spectrometry. Univariate statistical analyses, including independent t-test (adjusted for multiple comparisons), effect size (d > = 0.3) and single regression analyses were used to identify metabolites.

Results:

When comparing the black and white groups, the black group had lower body weight (p < 0.001) and protein intake (p = 0.014). Central systolic blood pressure was higher in the black group compared to the white group (p > 0.005), whereas left ventricular mass index was similar between the groups (p = 0.97). Three from a total of 192 metabolites were identified to be more abundant (p < 0.046) and inversely associated with left ventricular mass index in the black group only: hydroxyproline (beta = –0.24; p = 0.020), glycine (beta = –0.23; p = 0.025) and trimethylamine (beta = –0.22; p = 0.026).

Conclusions:

Higher urinary levels of hydroxyproline, glycine and trimethylamine were inversely associated with left ventricular mass index in the black adults only. Hydroxyproline and glycine are important in maintaining healthy collagen turnover and stability in the heart. Our results may reflect an increase in collagen biosynthesis and collagen deposition in the left ventricle due to higher central systolic blood pressure in the black population.
PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES CIRCULATING AND INTRATUBULAR ANGIOTENSIN II-INDUCED HYPERTENSION IN MICE
Authors: Li Xiao , Leite Ana Paulo , Zheng Xiaowen , Zhao Chunling , Zhang Liang , Chen Xu , Zhou Xinchun , Zhuo Jia
Published: April 2021

Objective:

The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors in the kidney, PT-Agtr1a-/-, to test the hypothesis that intratubular angiotensin II (Ang II) and AT1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II-induced hypertension.

Design and method:

To test our hypothesis, eight groups (n = 7–15 per group) of adult male wild-type, global Agtr1a-/-, and PT-Agtr1a-/-, and PT-Nhe3-/- mice were infused with Ang II (1.5 mg/kg/day, i.p.), or overexpressed an intracellular Ang II fusion protein (Ad-sglt2-ECFP/Ang II) in the proximal tubules of the kidney for 2 weeks. Basal blood pressure and the pressor responses, glomerular filtration rate (GFR) and 24 h urinary natriuretic response, and the pressure-natriuresis response were determined.

Results:

Basal telemetry blood pressure were ∼15 ± 3 mmHg lower in PT-Agtr1a-/- than wild-type mice and ∼13 ± 3 mmHg higher than Agtr1a-/- mice (P < 0.01). Basal glomerular filtration was ∼23.9% higher (P < 0.01), whereas fractional proximal tubule Na+ reabsorption was lower in PT-Agtr1a-/- mice (P < 0.01). Deletion of AT1a receptors in the proximal tubules augmented the pressure-natriuresis response (P < 0.01), and natriuretic responses to salt loading or Ang III infusion (P < 0.01). Ang II induced hypertension in wild-type, PT-Agtr1a-/- and PT-Nhe3-/- mice, but the pressor response was ∼16 ± 2 mmHg lower in PT-Agtr1a-/- and PT-Nhe3-/-mice (P < 0.01). Deletion of AT1a receptors or NHE3 in the proximal tubules attenuated ∼50% of Ang II-induced hypertension in wild-type mice (P < 0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT-Agtr1a-/- mice (P < 0.01).

Conclusions:

Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT1 (AT1a)/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II-induced hypertension.
BLOOD PRESSURE-LOWERING, ANTIHYPERTENSIVE TREATMENT AND INCIDENT DIABETES
Authors: Nazarzadeh Milad , Bidel Zeinab , Canoy Dexter , Copland Emma , Wamil Malgorzata , Byrne Karl Smith , Sundström Johan , Teo Koon , Davis Barry R. , Chalmers John , Pepine Carl J. , Dehghan Abbas , Bennet Derrick A. , Smith George Davey , Rahimi Kazem
Published: April 2021

Objective:

To investigate the effect of blood pressure lowering and specific antihypertensives on the risk of new-onset type 2 diabetes, leveraging the strengths of both genetic data and individual-level data from randomised trials of blood pressure-lowering treatments.

Design and method:

We pooled individual-level data of 145,939 participants from nineteen randomised clinical trials. We used stratified Cox proportional hazard models, with fixed treatment effects, and participants as the unit of analysis. Analyses were complemented with Mendelian randomisation studies using naturally randomised genetic variants associated with systolic blood pressure and genetic variants encoding the therapeutic targets of each drug class.

Results:

After a median of 4.4 years follow-up, 9,883 participants were diagnosed with new-onset diabetes in clinical trials. Blood pressure-lowering treatment was found to reduce the risk of diabetes by 11% (hazard ratio [HR] per 5-mm Hg reduction in systolic blood pressure 0.89 [95% confidence interval [CI] 0.84 to 0.95]). Similarly, in the Mendelian randomisation study, each 5-mm Hg genetically-influenced lower systolic blood pressure was associated with an 11% lower risk of diabetes (odds ratio [OR] 0.88 [95% CI 0.84 to 0.92]). Evidence from genetic data and trials were also consistent in that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduced the risk of diabetes, and beta-blockers increased this risk. There was no evidence of an effect for calcium channel blockers and findings for thiazide diuretics were inconsistent; while genetic analysis showed a reduction in risk, the mostly indirect estimation from network analysis of trials suggested an increased risk compared with placebo.

Conclusions:

We found consistent evidence supporting that lowering blood pressure reduces the risk of new-onset diabetes. However, this protective effect was not uniform among different antihypertensive classes. Whereas ACEIs and ARBs reduced the risk of new-onset diabetes, the converse was observed with beta-blockers and possibly with thiazide diuretics. In determining which class of drug to use to manage elevated blood pressure, consideration of diabetes risk may help inform clinical decision-making.
ANATOMY OF RENAL DENERVATION DURABILITY
Authors: Sharp Andrew , Tunev Stefan , Schlaich Markus , Lee David , Finn Aloke , Melder Robert , Trudel Julie , Kandzari David
Published: April 2021

Objective:

Safety and efficacy of catheter-based renal denervation (RDN) have been demonstrated in previous randomized, sham-controlled trials. Ongoing registries also suggest long-term durability of the RDN procedure. However, the exact mechanisms for RDN durability have not been previously elucidated. This report aimed to characterize the pathophysiological processes post radiofrequency (RF) RDN that translate into procedural durability utilizing animal models.

Design and method:

Animal studies were conducted in accordance with published guidelines. RDN was performed using the Symplicity RDN system (Medtronic, Santa Rosa, CA, USA) and the multielectrode RF Symplicity Spyral catheter in 164 healthy swine. Serial histological tissue samples were obtained 7, 28, 60, and 180 days post-procedure and followed by immunohistochemical and histopathologic analysis of RF-treated regions, sympathetic nerves and renal cortical axons.

Results:

At 7 days post-RDN, inflammation and swelling predominated the nerve lesions at the treatment site. A progressive nerve deterioration accompanied by Schwann cell reaction occurred over time leading to terminal atrophy and fibrosis at 180 days post-RDN. Nerve atrophy also became present distal to the treatment site. Although new Schwann cells appeared post-RDN, they failed to form the characteristic nerve fascicles and bundles which would reconstitute normal nerve morphology and support functional axons. Quantitative comparison of nerve necrosis and nerve atrophy indicated that proximal nerve necrosis peaks in the treated segments of the vessel, whereas nerve atrophy and low-grade nerve inflammation originates at the region of peak necrosis and extends distally beyond the RDN lesion. Thus, despite anatomic Schwann cell regeneration, the functional axonal nerve component did not recover.

Conclusions:

Histological analyses of porcine tissues demonstrated that terminal atrophy and fibrosis of the renal nerves developed within 180 days post-RF RDN procedure. Although new Schwan cell formation occurred, it did not reconstitute native nerve morphology suggesting functional nerve recovery is unlikely.
CARDIOVASCULAR OUTCOMES AND ALL-CAUSE MORTALITY ASSOCIATED WITH APPARENT TREATMENT-RESISTANT HYPERTENSION APPLYING THE 2017 ACC/AHA GUIDELINE
Authors: Jaejin An , Sim John , Lui Ran , Zhou Hui , Calhoun David , Wei Rong , Luong Tiffany , Reynolds Kristi
Published: April 2021

Objective:

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline lowered BP treatment goals from < 140/90 mmHg to < 130/80 mmHg for most adults with hypertension. We investigated cardiovascular (CV) outcomes and all-cause mortality associated with apparent treatment-resistant hypertension (aTRH) according to the 2017 ACC/AHA guideline.

Design and method:

We included adults aged > = 18 years identified from the 2014–2015 hypertension registry in a large US integrated healthcare system. aTRH was defined as either BP above goal while taking > = 3 classes of antihypertensive medication or taking > = 4 classes regardless of BP level. We identified individuals with non-aTRH, newly classified aTRH according to 2017 ACC/AHA, controlled and uncontrolled aTRH, and refractory hypertension (RH) (BP above goal with > = 5 classes). Individuals were followed from their first date meeting the aTRH criteria (aTRH group) or first date of entering the registry (non-aTRH group) until disenrollment from the health plan, the study end date (6/30/2019), or the outcomes of interest [composite CV events (myocardial infarction, stroke, and congestive heart failure), and death]. Multivariable Cox proportional hazards models were used to compare outcomes.

Results:

We included 450,181 individuals with treated hypertension [mean age 65 years, 46% White, 27% Hispanic, 14% Black, and 12% Asian], and 21% were considered as aTRH [5% newly classified aTRH, 3% controlled aTRH, 12% uncontrolled aTRH, and 1% RH]. The crude composite CV event rate was highest among patients with RH [RH = 39.9, controlled aTRH = 32.2, uncontrolled aTRH = 24.4, newly classified aTRH = 12.2, non-aTRH = 9.3 events per 1,000 person-years]. A higher risk of CV events was associated with aTRH compared with non-aTRH [Adjusted hazard ratios (HR) (95% CI) = 1.64 (1.60, 1.69)]. Newly classified aTRH was associated with higher CV events and all-cause mortality compared with non-aTRH [HR = 1.43 (1.35, 1.52) for CV events, 1.15 (1.09, 1.20) for all-cause mortality].

Conclusions:

Newly classified aTRH, per the 2017 ACC/AHA BP guideline, was associated with a higher risk of CV events compared with non-aTRH, which supports more stringent BP goals for individuals taking 3 or more classes of antihypertensive medication.
THE ASSOCIATION OF TESTOSTERONE IN UMBILICAL CORD BLOOD AND SYSTOLIC BLOOD PRESSURE IN OFFSPRING IN YOUNG ADULTHOOD
Authors: Beilin Lawrence , Le-Ha Chi , Mori Trevor , Hickey Martha , Keelan Jeffrey , Burrows Sally
Published: April 2021

Objective:

Animal studies have shown intrauterine androgen exposure leads to offspring adult cardiovascular dysfunction, including hypertension. In humans, androgens in umbilical cord blood at birth reflect the androgen environment in pregnancy.

In a population-based sample studied from in utero, we aimed to explore the association between prenatal testosterone exposure and BP in young adulthood.

Design and method:

In the Raine Study cohort, data was available on umbilical cord blood androgens and on BP, anthropometric and socio-behavioural information in 387 participants at 20 years and 319 at 27 years. Total testosterone was measured using liquid chromatography-tandem mass spectrometry; free testosterone, by empirical method (Sartorius et al.); and sex hormone binding globulin, by ELISA. Bioavailable testosterone (BioT; nmol L) was calculated employing the formula: BioT = free testosterone + albumin-bound testosterone. We employed hierarchical linear mixed effects regression, with maximum likelihood estimation, to assess the association of BioT with blood pressure at 20 and 27 years adjusting for potential confounders.

Results:

Umbilical cord BioT levels were significantly higher in males than in females (0.14 [95%CI 0.13; 0.16] vs 0.08 [95%CI 0.07; 0.09] nM/L; p < 0.001). Mean systolic BP were 122.9 (95%CI 121.3; 124.6) and 110.5 (95%CI 109.1; 111.9) mmHg at 20 years, and 122.4 (95%CI 120.7; 124.1) and 111.2 (95%CI 109.8; 112.7) mmHg at 27 years, in males and females, respectively. Longitudinal regression models showed higher BioT levels were positively associated with systolic BP (coefficient: 16.1 [95% CI: 1.8; 30.4]; p = 0.027) at both 20 and 27 years, after adjusting for BMI, sex and hormone contraceptive use. This translates to a 1 mmHg increase in systolic BP for a 1 standard deviation increase in BioT. There was no difference in this association between sexes.

Conclusions:

To our knowledge, this is the first population-based study that shows testosterone in umbilical cord blood at birth is significantly associated with systolic BP in young adulthood. Our data support previous findings in animal studies of a causal relationship. The data suggest that higher testosterone levels in utero may increase the risk of hypertension later in life.
LOW-DOSE FOLIC ACID PROTECTS AGAINST ADVERSE CARDIAC REMODELING IN SPONTANEOUSLY HYPERTENSIVE RATS WITH HYPERHOMOCYSTEINEMIA
Authors: Xu Rui , Cao Ping
Published: April 2021

Objective:

The interaction between hypertension and hyperhomocysteinemia (Hhcy) leads to adverse myocardial and coronary vascular remodeling in the hypertensive heart, resulting in impaired diastolic function. Folic acid (FA) is a free radical scavenger with antioxidant properties that effectively reduces homocysteine (Hcy) levels. The aim of this study was to evaluate whether lowering plasma homocysteine (Hcy) with different dose of folic acid (FA) could against Hhcy-induced myocardial injury in spontaneously hypertensive rats (SHRs) and its possible mechanisms.

Design and method:

Thirty-two adult male SHRs were randomly divided into four groups (n = 8/group), namely control group, Hhcy intervention group, Hhcy + Low-dose FA treatment group (0.4 mg/Kg·d), Hhcy + High-dose FA treatment group (4 mg/Kg·d), and then three Hhcy groups were subcutaneously injected 2% DL- homocysteine 5 ml/Kg. FA intervention started after 4 weeks’ Hcy injection. The total duration of the trial was 16 weeks. Cardiac echocardiography was performed at the last week. The Systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma Hcy, serum malondialdehyde (MDA), superoxide dismutase (SOD) were measured, and Masson's trichrome stain to enable evaluation of collagen deposition under a microscope. Furthermore, the levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) protein were detected by extraction of nuclear protein from cardiac tissue.

Results:

Intragastric administration of FA significantly reduced plasma Hcy levels. Serum SOD was significantly increased and serum MDA were also significantly attenuated by FA. Low-dose folic acid is more effective than high-dose folic acid in relieving Hhcy-induced anomalies in the heart of SHRs, such as the decline in cardiac diastolic function, perivascular collagen accumulation, and arteriolar wall thickening. FA increased the expression of Nrf2 and HO-1, and exhibited a protective effect against Hhcy-induced oxidative stress (OS), and there were no significant difference between high-dose and low-dose FA groups.

Conclusions:

Low-dose FA treatment can better protect against Hhcy-induced myocardial injury in SHRs, which may be due to its inhibition of OS and upregulation of Nrf2/HO-1 pathway.
CONTROL OF ANTIHYPERTENSIVE EFFECT MEDIATED BY SMALL INTERFERING RNA TARGETING ANGIOTENSINOGEN
Authors: Uijl Estrellita , Colafella Katrina M. Mirabito , Ren Liwei , Hoorn Ewout J. , Zlatev Ivan , Kim Jae B. , Huang Stephen , Melton Lauren , Foster Don , Danser A.H. Jan , Van Veghel Richard , Garrelds Ingrid M.
Published: April 2021

Objective:

A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and durable antihypertensive effect, lasting weeks to months in preclinical models. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion and reverse RNAi-mediated blood pressure lowering.

Design and method:

Spontaneously hypertensive rats on a low-salt diet (<0.03% NaCl) were treated for 4 weeks with siRNA (10 mg/kg fortnightly; s.c.), supplemented with fludrocortisone (6 mg/kg/day; s.c.), midodrine (4 mg/kg/day; s.c.) or a high-salt diet (4% NaCl) during the final 2 weeks (n = 6–7 per group). Before and after 2 weeks of siRNA, blood pressure responses to intravenous bolus injections of angiotensin II (0.05; 0.5 and 5 mg/kg) and noradrenalin (0.1; 1.0 and 10 mg/kg) were recorded via radiotelemetry in anaesthetised rats.

Results:

Baseline mean arterial pressure (MAP; 136 ± 3 mmHg) was lowered by 19 ± 1 mmHg by AGT siRNA in combination with a low-salt diet. Acute pressor responses to angiotensin II and noradrenalin were identical before and after siRNA. Fludrocortisone restored MAP to baseline levels (137 ± 3 mmHg), as did replacing the low-salt diet with a high-salt diet (139 ± 4 mmHg). Midodrine had no effect. Under low salt conditions, siRNA virtually abolished plasma AGT by 99.2 ± 0.1% to 6 ± 1 nM, and increased active plasma renin concentrations. AGT was not altered by midodrine, only marginally raised by high sodium intake, but increased to 20 ± 5% of pre-siRNA treatment levels by fludrocortisone, paralleled by near-elimination of plasma renin levels by 98 ± 1% to 2.1 ± 0.9 ng angiotensin I/mL/h.

Conclusions:

The efficacy of angiotensin II and noradrenaline to raise blood pressure is not affected by RNAi-mediated AGT suppression. Increased sodium intake or fludrocortisone may represent chronic, less invasive alternatives for controlling blood pressure during AGT depletion, of which the latter seems to be facilitated by amplification of AGT production.
HIGH FASTING BLOOD GLUCOSE LEVEL INCREASE RISK OF HYPERTENSION INCIDENCE INDEPENDENT OF INSULIN RESISTANCE IN JAPANESE: THE SAKU STUDY
Authors: Tatsumi Yukako , Asayama Kei , Morimoto Akiko , Sonoda Nao , Miyamatsu Naomi , Ohno Yuko , Miyamoto Yoshihiro , Izawa Satoshi , Ohkubo Takayoshi
Published: April 2021

Objective:

Although high fasting blood glucose (FBG) levels is reported to be a risk factor for incidence of hypertension, the predominant confounding effect of insulin resistance may make the current evidence difficult to apply for individuals without insulin resistance. This study aimed to investigate whether high FBG levels increase the risk of incidence of hypertension, regardless of insulin resistance.

Design and method:

This 5-year cohort study included 2210 Japanese aged 30–64 years without hypertension. Participants were stratified by baseline homeostasis model assessment of insulin resistance (HOMA-IR) less than 1.6, 1.7–2.4 and 2.5 or higher. In each HOMA-IR stratum, hazard ratios (HRs) and 95% confidence intervals (CIs) of FBG 7.0 mmol/l or higher for the incidence of hypertension compared with FBG less than 7.0mmol/l were estimated using multivariable-adjusted Cox proportional hazard models. Hypertension was defined as blood pressure 140/90 mmHg or higher or receiving antihypertensive treatment.

Results:

Of 2210 participants, 334 participants showed increased BP levels to 140/90 mmHg or higher, and 212 participants started taking antihypertensive treatment during the median 4.9-year follow-up period (interquartile range: 3.5–5.0 years). After adjustment for age, sex, overweight, dyslipidaemia, smoking status, alcohol consumption, physical activity, family history of hypertension, and systolic BP at baseline, the HRs (95% CIs) of FBG 7.0 mmol/l or higher compared with FBG less than 7.0mmol/l were 1.94 (1.05–3.59), 2.94 (1.36–6.36) and 2.22 (1.03–4.78) in those with HOMA-IR less than 1.6, 1.7–2.4 and 2.5 or higher, respectively.

Conclusions:

FBG 7.0 mmol/l or higher increased future incidence of hypertension compared with FBG less than 7.0 mmol/l in middle-aged Japanese, regardless of insulin resistance defined by HOMA-IR.
HYPOTENSIVE EFFECTIVENESS OF THE INTRARENAL MEDULLARY ENDOTHELIN ETA RECEPTOR BLOCKADE IN THE TWO ANIMAL MODELS OF HYPERTENSION
Authors: Badzynska Bozena , Sadowski Janusz , Vaneckova Ivana , Kompanowska-Jezierska Elzbieta
Published: April 2021

Objective:

Endothelin-1 (ET-1) is involved in the pathogenesis of arterial hypertension and chronic kidney disease, however, its mechanism of action is unclear. ET-1 is known to act via ETA and ETB receptors; their activation leads, respectively, to constriction or NO-mediated dilation of the systemic and renal vasculature. ET-1 levels are elevated in experimental and in human hypertension. Here we examined the effects of ETA receptor blockade with atrasentan, administered intravenously (i.v.) or directly to the renal medullary interstitium (i.med.) in two models of rat hypertension.

Design and method:

In anaesthetized rats with hypertension induced by uninephrectomy followed by high-salt (4% Na w/w) diet (HS/UNX) and in spontaneously hypertensive rats (SHR) we measured mean arterial pressure (MAP), total renal blood flow (RBF, renal artery probe), renal medullary blood flow (MBF, laser-Doppler flux), and renal medullary nitric oxide (NO) signal. Atrasentan doses were: 0.6 mg/kg/h i.v. or 0.12 mg/kg/h i.med.

Results:

In HS/UNX intravenous atrasentan reduced MAP (142 ± 7 to 117 ± 8 mmHg, p < 0.001) and increased NO signal by 12% (p < 0.05). RBF fell from 25.6 ± 1.7 to 22.3 ± 1.6 ml/min (p < 0.03). Intramedullary atrasentan decreased MAP (127 ± 6 to 115 ± 6, p < 0.04) and increased NO signal by 9.7% (p < 0.03). RBF and MBF did not change significantly. In SHR intravenous atrasentan decreased MAP (171 ± 3 to 152 ± 9 mmHg, p < 0.03) and RBF (6.4 ± 0.5 to 5.0 ± 0.4 ml/min, p < 0.02); NO signal increased by 9.1% (p < 0.01). Intramedullary atrasentan decreased MAP (176 ± 4 to 167 ± 7 mmHg, p < 0.001); NO increased by 10% and MBF by 26% (p < 0.02–0.05). Evidently, in both hypertension models atrasentan always decreased MAP and increased tissue NO.

Conclusions:

To summarise, in both hypertension models blockade of ETA receptors decreased MAP, reflecting systemic vasodilation. The pressure decrease was followed by a decrease in RBF, probably the result of reduced renal perfusion pressure and imperfect autoregulation. Remarkably, MAP decrease was also seen with intramedullary ETA blockade but then without impairment of renal circulation. Of particular interest was a regular increase in tissue NO: we propose that the blockade of ETA unmasked the action of unbound ET-1 via ETB receptors, leading to NO release.
NOX4 PROTECTIVE EFFECT IN ENDOTHELIAL FUNCTION INVOLVES ACTIVATION OF TRANSIENT RECEPTOR POTENTIAL MELASTATIN 2 (TRPM2) CATION CHANNEL
Authors: Alves-Lopes Rheure , Neves Karla , Montezano Augusto , Touyz Rhian
Published: April 2021

Objective:

Nox4 regulates endothelium-dependent relaxation through production of H2O2, which in turn acts as an EDHF. We demonstrated that TRPM2 is also a target of H2O2 in vascular cells. TRPM2 is a redox-sensitive Ca2+ channel and once activated leads to Ca2 influx. Hypertension-associated endothelial dysfunction involves reduction in eNOS activation and is potentiated in the absence of NOX4. As TRPM2 channel is a H2O2 sensor and regulates Ca2+ entry, we questioned whether impaired vascular relaxation in hypertensive NOX4 KO mice involves the H2O2-TRPM2-Ca2+ axis in endothelial cells.

Design and method:

WT and TTRhRen hypertensive mice were crossed with Nox4 KO mice. Vascular function was measured by wire myograph in resistance arteries. Ca2+ influx was assessed by fluorescence microscopy in aortic endothelial cells. eNOS activation was assessed by immunoblotting.

Results:

Blood pressure was significantly increased in TTRhRen (130.3 ± 7.0 mmHg) and TTRhRen/NOX4 KO mice (141.3 ± 18 mmHg) versus control mice (98.1 ± 8.0 mmHg). TTRhRen mice had reduced endothelium-dependent relaxation (Emax: WT 83.5 ± 4.03 vs TTRhRen 59.1 ± 3.5); an effect worsened by NOX4 KO (37.9 ± 5.4), p<0.05. The TRPM2 activator, ADPR, improved vascular relaxation in TTRhRen/NOX4 KO mice (75.9 ± 7.7); an effect recapitulated by H2O2 (74.2 ± 15.4), p < 0.05. Ang II-induced Ca2+ influx in endothelial cells, important in eNOS activation, was reduced by TRPM2 inhibitors (AUC - Ca2+: 8-br-cADPR 76161 ± 1052.0; Olaparib 74763 ± 843.2 and 2-APB 79625 ± 277.4, p < 0.05) and the NOX1/4 inhibitor GKT137831 (AUC - Ca2+: Ang II 107357 ± 1940.2 vs GKT 60270 ± 255.6, p < 0.05). Ang II-induced activation of eNOS (Ser1177) (%: 72.3 ± 24.7) was blocked by GKT137831, PEG-catalase and the TRPM2 inhibitor 8-br-cADPR (p < 0.05).

Conclusions:

Endothelial dysfunction in TTRhRen mice involves impaired TRPM2 activation. Inhibition/downregulation of Nox4 and reduced bioavailability of H2O2 exacerbates these processes. We identify a novel protective effect of NOX4 in endothelial cells involving H2O2-mediated activation of TRPM2-Ca2+-eNOS signalling.
INFLUENCE OF RENAL FUNCTION ON RETINAL VASCULAR DENSITY ASSESSED BY OCT ANGIOGRAPHY IN HYPERTENSIVE PATIENTS
Authors: Mulè Giuseppe , Vadalà Maria , Guarrasi Giulia , Guarino Laura , Castellucci Massimo , Sorce Alessandra , Dell’Utri Riccardo , Ferotti Alessandra , Cillino Salvatore , Cottone Santina
Published: April 2021

Objective:

It is well known that the retinal vasculature may be considered as a window through which the body microcirculation can be easily, safely and repeatedly, observed. Alterations of the renal microcirculation have been documented in animal models with hypertensive renal damage and microvasculature changes have been suggested to play a mayor etiological role in a large proportion of subjects with chronic CKD. Angio OCT is a recently developed noninvasive diagnostic imaging technique that employs motion contrast extracted from high-speed OCT images to produce depth-resolved, high-resolution images of retinal and choroidal vasculature without dye injection.

Aim:

Our study was aimed to assess in hypertensive patients the influence of renal function on retinal vascular density assessed by Angio-OCT.

Design and method:

We enrolled 120 consecutive hypertensive subjects (age: 51 ± 13 years; males 68%) attending our Hypertension Centre. All the patients underwent routine biochemical evaluation and angio-OCT. The retinal angiograms obtained allowed to assess vascular density of both superficial (DRS) and deep (DRP) network in the parafoveal area. Only one eye of each subject was randomly selected for analysis. Glomerular filtration rate was estimated by CKD-EPI equation.

Results:

26 subjects showed a GFR value < 60 ml/min/ 1.73 m2. These patients, when compared to those with higher GFR, showed significantly lower values of DRS (36.48 ± 1.23 vs 37.29 ± 0.78 %; p < 0.001) and of DRP (37.69 ± 1.23 vs 38.34 ± 0.97 %; p = 0.005). Moreover, the GFR correlated directly with DRP (r = 0.385; p < 0.001) and with DRS (r = 0.247; p < 0.01). These associations remain statistically significant even after adjustment for age, BP and other confounders in multiple linear regression analyses (respectively, beta = 0.265; p < 0.05 e beta 0.211; p < 0.05).

Conclusions:

Our study, showing a significant association between reduced retinal vascular density and renal function impairment, confirms the close link relating CKD with retinal vascular abnormalities.
DONEPEZIL IMPROVES VASCULAR FUNCTION IN A MOUSE MODEL OF ALZHEIMER'S DISEASE
Authors: Masi Stefano , Antonioli Luca , Duranti Emiliano , Fornai Matteo , Pellegrini Carolina , Baldacci Filippo , Taddei Stefano , Blandizzi Corrado , Virdis Agostino
Published: April 2021

Objective:

Donepezil represents the most effective drug in the treatment of Alzheimer's Disease (AD). Recent reports suggest that it might have free radical scavenging properties, which could potentially improve the vascular alterations commonly associated with AD and partially account for the cognitive benefits observed during treatment. However, the potential effect of donepezil on vascular function and structure remains largely unexplored.

Objective:

to assess the impact of donepezil on the vascular phenotype of an established model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone).

Design and method:

3 groups of animals were included: SAMP8 (n = 4), SAMP8 treated with Donepezil for 8 weeks (n = 4) and SAMR1 (Senescence-Accelerated Mouse-Resistant, a mouse model which does not develop the disease, n = 4). Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests, animals were euthanized, their mesenteric arteries were isolated and mounted on a pressurised myograph to assess endothelial function by means of dose-response curves to acetylcholine (Ach) alone or in combination with L-NAME or Vitamin C. Media-to-lumen ratio (M/L ratio) was also measured. In subsequent experiments (n = 4), donepezil was coincubated directly on the arteries isolated from untreated SAMP8 together with Ach.

Results:

Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated the cognitive dysfunction. SAMP8 had higher M/L ratio than SAMR1 and donepezil treated animals (p < 0.001 for both differences, Fig. 1). Endothelial function was impaired in SAMP8 animals compared to SAMR1 (Fig. 1). Addition of Vitamin C improved the vasodilatory response to Ach in SAMP8 (p < 0.001 vs Ach alone). Treatment with donepezil improved endothelial function in SAMP8 animals (p < 0.001 vs untreated SAMP8) and reduced the additional vasodilation induced by Vitamin C (Fig. 1). Acute incubation of mesenteric arteries from SAMP8 animals with donepezil induced a significant improvement of endothelial function from baseline (p < 0.001)and the subsequent addition of Vitamin C did not induce further vasodilation.

Conclusions:

The beneficial effects of donepezil on vascular function and structure might provide a novel mechanism explaining its positive effects on cognitive decline. These effects might be mediated by antioxidant mechanisms.
ALCOHOL – THE MYTH OF CARDIOVASCULAR PROTECTION
Authors: Schutte Rudolph , Wannamethee Goya
Published: April 2021

Objective:

We investigated three potential errors embedded in epidemiological evidence that could mask the health effects of alcohol, i.e., by using abstainers as reference group, combining alcohol from all drink types, and including protective relationships with ischemic heart disease when assessing overall cardiovascular (CV) risk.

Design and method:

The UK Biobank cohort consists of over 500,000 participants that attended one of 22 assessment centers across the United Kingdom. We calculated baseline alcohol intake as grams per week and followed CV outcomes for a median 6.9 years.

Results:

Never drinkers were at higher risk for all CV events (P < 0.0001), ischemic heart disease (P < 0.0001) and cerebrovascular disease (P < 0.0001). Alcohol from all drink types combined and beer/cider and spirits combined predicted CV events (both P < 0.024) and cerebrovascular events (both P < 0.011). Associations were stronger for beer/cider and spirits for both CV events (hazard ratio, 1.24 vs 1.08, P < 0.0001) and cerebrovascular events (hazard ratio, 1.30 vs 1.15, P < 0.0001). No relationships existed with ischemic heart disease (both P > 0.11). Wine was protective for CV events (P = 0.008) and ischemic heart disease (P < 0.0001), but not cerebrovascular events (P = 0.34). Excluding ischemic heart disease events resulted in the nullification of CV protection from wine (P = 0.95), while alcohol captured from beer/cider and spirits remained predictive (P < 0.0001).

Conclusions:

The use of abstainers as reference group, combining of all drink types including wine when capturing alcohol intake, and embedding the protective relationship between ischemic heart disease and wine in CV risk prediction, masks the health risks associated with alcohol intake and falsely portrays alcohol as protective.
CENTRAL SYSTOLIC BLOOD PRESSURE RELATES INVERSELY TO NITRIC OXIDE SYNTHESIS IN YOUNG BLACK ADULTS: THE AFRICAN-PREDICT STUDY
Authors: Craig Ashleigh , Mels Catharina Mc , Tsikas Dimitrios , Boeger Rainer H. , Schwedhelm Edzard , Schutte Aletta E. , Kruger Ruan
Published: April 2021

Objective:

Lower nitric oxide bioavailabilty associates with hypertension in diseased and elderly populations. With hypertension known to develop earlier in black populations, we compared both plasma and urinary nitric oxide-related markers and their associations with central systolic blood pressure and arterial stiffness in healthy young black and white adults.

Design and method:

We included healthy black and white men and women (n = 1110; 20–30 years) and measured central systolic blood pressure and pulse wave velocity, along with both plasma and urinary arginine, homoarginine, asymmetric dimethylarginine, symmetric dimethylarginine, as well as urinary ornithine/citrulline, nitrite and nitrate. Additionally, the urinary nitrate-to-nitrite ratio was calculated.

Results:

The black men and women had higher central systolic blood pressure and higher plasma arginine and asymmetric dimethylarginine, but lower urinary nitrate and urinary nitrate-to-nitrite ratio (all p< = 0.003) than their white counterparts. In single and forward stepwise multiple regression analyses, we found an inverse association of central systolic blood pressure (adj. R2 = 0.124; β= –0.134; p = 0.006) and plasma homoarginine in black men. Central systolic blood pressure associated inversely with urinary nitrate-to-nitrite ratio in black women only (adj. R2 = 0.171; β= –0.130; p = 0.029). In the white women, central systolic blood pressure associated positively with urinary asymmetric dimethylarginine (adj. R2 = 0.372; β= 0.162; p = 0.015). Pulse wave velocity associated inversely with plasma asymmetric dimethylarginine (adj. R2 = 0.253; β= –0.163; p = 0.024) in the white women only.

Conclusions:

The lower nitric oxide synthesis and the higher central systolic blood pressure in our black cohort support the notion of a potential increased risk for future large artery stiffness and hypertension development in later life.