bluuebunny/crossref_metadata_2025_split huggingface dataset:
INTERACTION BETWEEN TRPM7 AND EPIDERMAL GROWTH FACTOR RECEPTOR MEDIATES VASCULAR SMOOTH MUSCLE CELL ACTIVATION AND PROLIFERATION
Authors: Zou Zhiguo , Rios Francisco , Neves Karla B. , Alves-Lopes Rheure , Ling Jiayue , Baillie George , Camargo Livia L. , Gudermann Thomas , Chubanov Vladimir , Montezano Augusto C. , Touyz Rhian M. 
Published: April 2021

Objective:
Epidermal growth factor (EGF) binds to EGF receptor (EGFR) and stimulates multiple vascular signaling pathways. Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein (channel+enzyme, termed chanzyme) playing an important role in vascular homeostasis. Previous studies in renal cells demonstrated interactions between EGFR and TRPM6, a homologue of TRPM7. Here we questioned the importance of TRPM7 in EGF-mediated effects on vascular smooth muscle cell (VSMC) function.

Design and method:
Primary cultured VSMCs were isolated from humans and rodent models. Rat VSMCs (rVSMCs) and human VSMCs (hVSMCs) were stimulated with EGF (50ng/ml) in the absence/presence of gefitinib (1 μM), PP2 (10 μM), 2APB (30 μM) and NS8593 (40 μM), inhibitors of EGFR, c-Src kinase and TRPM7 respectively. Aorta were isolated from wild type (WT), TRPM7 kinase-deficient (TRPM7+/-kinase), and TRPM7 kinase-dead (TRPM7R/R) mice. Protein expression was investigated by immunoblotting. Intracellular Ca2+ and Mg2+ were assessed using fluorescence microscopy and flow cytometry respectively. EGFR-TRPM7 interaction was explored by proximity ligation assay (PLA) and immunoprecipitation. VSMC migration and proliferation were assessed by wound-healing assay and CFSE proliferation studies.

Results:
In hVSMC and rVSMC, EGF increased TRPM7 expression (47%) and phosphorylation (21%), p < 0.05 vs control; effects abolished by gefitinib and PP2. EGF-induced Mg2+ and Ca2+ influx was attenuated by gefitinib (4% and 8% respectively), NS8593 (5% for Mg2+) and 2-APB (6% and 13% respectively). EGF enhanced ERK1/2 phosphorylation (3-fold) in rVSMCs through c-Src, EGFR and TRPM7, p < 0.05. Cell migration (26%) and proliferation (17%) were enhanced by EGF, and reduced by inhibitors of EGFR, TRPM7 and ERK1/2, p < 0.05. EGF induced TRPM7-EGFR interaction, primarily in the cell membrane. VSMCs from TRPM7+/-kinase showed reduced EGFR expression (73%), phospho-c-Src (22%), and phospho-ERK1/2 (90%). Aortas from TRPM7R/R exhibited reduced phospho-EGFR (63%) and phospho-ERK1/2 (36%). Vessels from TRPM7+/-kinase showed reduced wall thickness.

Conclusions:
Our findings demonstrate important cross talk between EGFR and TRPM7. EGF/EGFR is both upstream and downstream of TRPM7. This interaction, which involves c-Src, regulates VSMC migration and proliferation. We identify a novel EGFR:TRPM7 pathway that may play an important role in vascular function and remodeling.
RETURN OF NERVE FUNCTION FOLLOWING RENAL DENERVATION IN THE PRESENCE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Walton Sarah , Parkington Helena , Kwok Edmund , Denton Kate 
Published: April 2021

Objective:
Regrowth of renal nerves and functional restoration occurs following renal denervation (RDN). There is little information regarding the impact of concomitant anti-hypertensive therapies on the extent of reinnervation following RDN. Angiotensin-II has previously been shown to promote renal vessel innervation. We hypothesised that angiotensin-converting enzyme inhibition (ACEi) prolongs the antihypertensive effects of RDN by delaying renal nerve regrowth. The aim of this study was to examine the effect of ACEi treatment on the return of nerve function at 12-weeks post-RDN in spontaneously hypertensive rats (SHR).

Design and method:
Male SHRs (∼12 weeks of age, n > 7/group) were implanted with a radiotelemetry probe to record mean arterial pressure (MAP). Rats were infused with enalapril (1 mg/kg/day s.c.) or vehicle for two weeks. Rats then underwent sham or surgical RDN procedures and ACEi/vehicle infusion continued for an additional 12 weeks following RDN. Vascular contraction to perivascular nerve stimulation in renal lobar arteries was assessed using wire myography to determine the extent of renal nerve function return.

Results:
ACEi and RDN independently caused an immediate and sustained reduction in MAP (ACEi: -12 ± 3 mmHg, RDN: -19 ± 4 mmHg, both P < 0.05) across the 12-week period compared to untreated counterparts. However, the blood pressure-lowering effect of RDN was not enhanced by concomitant ACEi. Heart mass was ∼16% less in ACEi-RDN rats compared to untreated counterparts. Return of neurovascular function was observed in RDN-treated rats, but levels were only partially restored to that of untreated rats (P < 0.001). ACEi alone attenuated the response to perivascular nerve stimulation (P < 0.05) but the effects of ACEi in combination with RDN were not additive.

Conclusions:
Here we show partial functional reinnervation is evident 12 weeks following RDN in the SHR. This may account for the sustained reduction in MAP following RDN. ACEi infusion alone attenuated neurovascular function, but ACEi combined with RDN did not affect the return of renal neurovascular function. These findings suggest that RDN and ACEi effectively lower blood pressure in the long term and may confer cardioprotective benefits despite the return of nerve function. However, ACE inhibition does not provide additive benefits to delaying renal reinnervation.
VISIT-TO-VISIT GLOMERULAR FILTRATION RATE VARIABILITY AS A PREDICTOR FOR CARDIOVASCULAR AND RENAL OUTCOMES IN ESSENTIAL HYPERTENSION: DATA FROM A GREEK 8-YEAR-FOLLOW-UP STUDY
Authors: Laina A. , Tsioufis K. , Dimitriadis K. , Kasiakogias A. , Liatakis I. , Koutra E. , Leontsinis I. , Konstantinidis D. , Kouremeti M. , Dri E. , Iliakis P. , Vogiatzakis N. , Thomopoulos K. , Tousoulis D. 
Published: April 2021

Objective:
Renal dysfunction is related with adverse prognosis in hypertension, however scarce data exist on the predictive value of kidney function variability on cardiovascular and renal outcomes in this setting. This study aims to assess the prognostic role of visit-to-visit glomerural filtration rate (GFR) variability on the incidence of coronary artery disease (CAD), stroke and end-stage renal disease in hypertensive patients.

Design and method:
We followed 2380 essential hypertensives (mean age 58.9 years, 1240 males, office blood pressure 144/91mmHg) free of cardiovascular disease for a mean period of 8 years. All subjects had at least one annual visit and blood sampling was performed in all visits for GFR estimation. We calculated standard deviation (SD) of mean GFR from visits 6months onward in patients with >or = 5 visits during follow-up. CAD was defined as the history of myocardial infarction or significant coronary artery stenosis revealed by angiography or coronary revascularization procedure, while stroke was defined as rapid onset of a new neurological deficit persisting at least 24 hours unless death supervened confirmed by imaging findings. End-stage renal disease was defined as GFR<15 mL/min/1.73 m2 or the need for long-term dialysis or transplantation.

Results:
The incidence of CAD, stroke and end-stage renal disease over the follow-up period were 2.8% (n = 68), 1.09% (n = 26) and 0.6% (n = 14). Hypertensives who developed CAD (n = 2312) had at baseline higher left ventricular mass index (115.7 ± 24.6 vs 103.7 ± 27.3 g/m2, p < 0.0001) compared to those who did not, whereas there was no difference with respect to baseline GFR (78 ± 19.6 vs 79.3 ± 18.6 mL/min/1.73 m2 (p = 0.573). In multivariate Cox regression models visit-to-visit glomerular filtration rate predicted end-stage renal disease (hazard ratio = 1.758, p = 0.01) but not CAD and stroke (p = NS for both). Baseline left ventricular mass index independently predicted CAD (hazard ratio = 1.042, p = 0.015) and stroke (hazard ratio = 1.035, p = 0.002).

Conclusions:
In essential hypertensive patients GFR variability predicts future development of end-stage renal disease but exhibits no independent prognostic value for CAD and stroke. These results suggest that fluctuations of renal function are related with damage at the kidneys and not at the cardiac and cerebrovascular level.
INCREASED CARDIOVASCULAR DEATH RATES IN A COVID-19 LOW PREVALENCE AREA
Authors: Del Pinto Rita , Desideri Giovambattista , Mammarella Leondino , Abballe Stefano , Dell’Anna Sofia , Cicogna Sabrina , Grassi Davide , Sacco Simona , Ferri Claudio 
Published: April 2021

Objective:
Preliminary data indicate a reduction in hospitalizations for acute coronary syndromes during the Covid19 outbreak in Northern Italy. We investigated whether the albeit marginal Covid19 burden in the province of L Aquila, in Central Italy, had an impact on cardiovascular hospitalizations and outcomes.

Design and method:
We retrospectively analyzed de-identified data from all patients admitted to the five hospitals located in the province of L Aquila for all-cause and cardiovascular hospitalizations, cardiovascular acute phase treatments (coronary angioplasty, systemic fibrinolysis, endovascular procedures), and in-hospital cardiovascular deaths in the time window from January 1 to March 31, in the years 2020 (study period) and 2019 (control period). Unadjusted incidence rate ratios (IRR) comparing study/control period for the number of admissions/procedures were calculated through Poisson regression. Case fatality rate (%) for cardiovascular diseases in the examined periods was assessed.

Results:
5908 patients were hospitalized in the first quarter of 2020 (52.9% women, mean age 59.2 ± 24.9 years, 64.9 mean daily admissions). In the same period in 2019, 6852 patients were hospitalized (51.8% women, mean age 60.1 ± 24.6 years; 76.1 mean daily admissions). Significantly less all-cause and cardiovascular hospitalizations occurred in the study period than in the control period (IRR 0.85, 95%CI 0.82–0.88; IRR 0.73, 95%CI 0.67–0.80, respectively). The mean daily number of cardiovascular procedures was also lower (IRR: 0.74, p = 0.009). Importantly, a disproportionate decrease in the number of procedures was observed in relation to cardiovascular hospitalizations in the study period (13.8% versus 19.3%, p = 0.001). More intra-hospital cardiovascular deaths occurred in March 2020 (11.9%) compared with March 2019 (6.1%) (p = 0.048).

Conclusions:
Changes in healthcare seeking behaviors and an increased burden of cardiovascular-related deaths occurred in a Covid19 low prevalence Italian area. Besides unmeasured factors, including forced lifestyle changes, late hospital presentations and consequent greater disease severity might have affected eligibility and outcome of cardiovascular procedures. This evidence advances recent concerns regarding the impact of the pandemic on cardiovascular diseases and related deaths.
EVIDENCE OF A BLOOD PRESSURE REDUCTION DURING THE COVID-19 ASSOCIATED LOCKDOWN: A PLAUSIBLE EXPLANATION FOR THE OBSERVED DECLINES IN ACUTE CARDIOVASCULAR DISEASES?
Authors: Girerd Nicolas , Meune Christophe , Duarte Kevin , Vercamer Vincent , Lopez-Sublet Marilucy , Mourad Jean-Jacques 
Published: April 2021

Objective:
The Covid-19 pandemic has been associated with a marked reduction in the incidence of cardiovascular diseases. The main objective of the study was to quantify the changes in blood pressure (BP) and heart rate (HR) prior to and after initiation of the lockdown.

Design and method:
A big data analysis of BP and HR measurements recorded during the lockdown period versus measurements during the Covid-19 period prior to confinement as well as versus measurements recorded in 2019. All participants were from the Paris urban area. Subjects used a Withings connected home blood pressure monitor and had at least one measurement prior to and during the lockdown and in 2019.

Results:
A total of 297,089 BP recordings were available from 2273 participants (age 56.3 ± 12.8 years, 81.1% male). Recording frequency was similar before and during the lockdown. BP gradually decreased during the first 4 weeks of confinement, reaching a decrease of 3 mmHg (-2.4 to -3.9) in systolic BP (SBP) and 1.5 mmHg (-1.4 to -2.2) in diastolic BP (DBP) from week 4 to week 7 (all p < 0.001). Age and sex-adjusted comparisons yielded similar results. Participants with higher SBP and DBP had a greater decrease in SBP and DBP during the lockdown (p < 0.0001 each); age and gender had no significant effect. No significant variation in HR was detected during the studied periods.

Conclusions:
Our study demonstrates a progressive decrease in SBP and DBP during the lockdown that may partly explain the concomitant reported reduction in the incidence of acute cardiovascular diseases.
ASSOCIATION OF HYPERTENSION WITH ALL-CAUSE MORTALITY AMONG HOSPITALIZED PATIENTS WITH COVID-19
Authors: Rodilla Enrique , Saura Alberto , Jiménez Iratxe , Mendizábal Andrea , Pineda-Cantedo Araceli , Lorenzo-Hernández Elizabeth , Fidalgo-Montero Maria Del Pilar , López-Cuervo Joaquín Fernández , Gil-Sánchez Ricardo , Rabadán-Pejenaute Elisa , Abella-Vázquez Lucy , Giner-Galvañ Vicente , Solís-Marquínez Marta Nataya , Boixeda Ramon , Peña-Fernández Andrés De La , Carrasco-Sánchez Francisco Javier , González-Moraleja Julio , Torres-Peña José David , Guisado-Espartero María Esther , Escobar-Sevilla Joaquín , Guzmán-García Marcos , Martín-Escalante María Dolores , Martínez-González Ángel Luis , Casas-Rojo José Manuel , Gómez-Huelgas Ricardo 
Published: April 2021

Objective:
It is unclear to which extent the higher mortality associated with hypertension in the coronavirus disease (COVID-19) is due to its increased prevalence among older patients or to specific mechanisms. The main objective of the study is to analyze whether HT represents an independent risk factor for death as a hard endpoint in patients hospitalized with SARS-CoV-2 in Spain.

Design and method:
Cross-sectional, observational, retrospective multicenter study, analyzing 12226 patients who required hospital admission in 150 Spanish centers included in the nationwide SEMI-COVID-19 Network. We compared the clinical characteristics of survivors versus non-survivors.

Results:
The mean age of the study population was 67.5 ± 16.1 years, 42.6% were women. Overall, 2630 (21.5%) subjects died. The most common comorbidity was hypertension (50.9%) followed by diabetes (19.1%), and atrial fibrillation (11.2%). Multivariate analysis showed that after adjusting for gender (males, OR: 1.5, p = 0.0001), age tertiles (second and third tertiles, OR: 2.0 and 4.7, p = 0.0001), and Charlson Comorbidity Index scores (second and third tertiles, OR: 4.7 and 8.1, p = 0.0001), hypertension was significantly predictive of all-cause mortality when this comorbidity was treated with angiotensin-converting enzyme inhibitors (ACEIs) (OR: 1.6, p = 0.002) or other than renin-angiotensin-aldosterone blockers (OR: 1.3, p = 0.001) or angiotensin II receptor blockers (ARBs) (OR: 1.2, p = 0.035).

Conclusions:
The preexisting condition of hypertension had an independent prognostic value for all-cause mortality in patients with COVID-19 who required hospitalization. ARBs showed a lower risk of lethality in hypertensive patients than other antihypertensive drugs.
HYPERTENSION AND COVID-19: THE POSSIBLE ROLE OF METALLOPROTEINASE-9 IN COVID-19 PATHOPHYSIOLOGY
Authors: Mesquita Carolina Dávila , Do Couto Ariel Emiliano Souza , Campos Ligia Borges , Mora Bruno Cesar Petroski , Mestriner Fabiola , Vasconcelo Tauana Fernandes , Barbosa Jessyca Michelon , Corsi Carlos Curylofo , Ferro Denise , Ribeiro Mauricio Serra , Menegueti Mayra Gonçalves , Martins M. Auxiliadora , Becari Christiane 
Published: April 2021

Objective:
The pathophysiological mechanism of acute lung injury in COVID-19 includes a cascade of local and systemic responses with activation of several pro-inflammatory cytokines, including metalloproteinases. The aim of this study is investigate the role of matrix metalloproteinase-9 (MMP-9) in plasma from patients with severe COVID-19 hospitalized in a Brazilian ICU.

Design and method:
The study was designed to analyze the MMP-9 plasmatic in COVID-19 severe infection. Epidemiological data and blood samples were obtained from 42 subjects hospitalized in the ICU with clinically SARS-CoV-2 infection confirmed by RT-PCR (COVID), and 15 healthy subjects (Control). Zymography methods obtained the MMP-9 plasma activity. Continuous variables are shown by mean ± STDV and analyzed by the Mann-Whitney test. Categorical variables were compared by the Chi-squared test. The MMMP-9 activity is shown in the log of normalized and analyzed by unpaired T-test. Two-way ANOVA was used to analyze subgroups divided by gender, age greater or less than the median 60.4-year-old, hypertensive or normotensive, non-obese or obese.

Results:
The COVID and Control groups did not differ significantly by age (62.6 ± 13vs.57.6 ± 12.2 years old, p = 0.097) and BMI (30.3 ± 6.1vs.29.33 ± 5.7 kg/m2, p = 0.338). The COVID group has fewer women than the Control group (28.6%vs.80%, p = 0.0008). The COVID subjects with hypertension were 42% vs.67% in the Control group (p = 0,2), and diabetes was similar in both groups. The hospital stay in the COVID group was 14.5 ± 11.5 days and the hospitalization death rate was 32.5%.
The COVID-19 group has shown an increase in MMP-9 activity compared with the Control group (0.38 ± 0.072 UA; 95%CI = 0.23–0.52,p < 0.0001). The MMP-9 activity increasing was independent of gender (p = 0.45), age (p = 0.93), BMI (p = 0.3) or hypertension (p = 0.6) and dependent of the COVID-19 infection (p < 0.0001). Therefore, our data are showing that the COVID-19 infection was responsible for MMP-9 improvement in plasma of severe COVID-19 infection (p < 0.0001) while all different analyses consistently showed a significant effect of COVID-19 infection (p < 0.0001).

Conclusions:
There is a significant increase in the MMP-9 plasmatic activity in severe COVID-19 patients independently of sex, age, obesity, and hypertension. Therefore, MMP-9 may be a potential new target for acute lung injury therapy in patients with COVID-19.
RNA-SEQ REVEALS HSP90 AS A REGULATOR FOR INTERLEUKIN 6-MEDIATED ACTIVATION OF NCC VIA THE MINERALOCORTICOID RECEPTOR
Authors: Moseley Auriel , Zhang Michelle , Tansey Malu , Ko Ben , Eaton Douglas , Wynne Brandi 
Published: April 2021

Objective:
Hypertension (HTN) is characterized by increased Na+ reabsorption and systemic inflammation including increased cytokines such as IL6. Clinically, IL6 is increased in hypertensive patients. Previous data from our laboratory has revealed a mechanism for IL6-mediated activation of the mineralocorticoid receptor (MR), leading to increased Na+ transporter activation and HTN via reactive oxygen species (ROS) and Rac1. We hypothesized that IL6 induces a specific transcriptome in the late distal nephron (DCT2) and used RNA-seq to investigate.

Design and method:
Mouse DCT2 (mDCT15) cells were treated with IL6 (100ng/mL, 24hrs) or vehicle (n = 4, each), then total RNA isolated. Data from the Illumina-sequenced transcriptome underwent comparative analysis to identify significant differentially expressed transcripts between vehicle and IL6 treated cells.

Results:
Differential gene expressed revealed multiple targets, including HSP90 (3.03x10-6, p-adj) encoding for heat shock protein (HSP) 90. HSP90 has been previously shown as crucial for ligand binding, MR nuclear translocation and activation.
To investigate whether inhibition of HSP90 would affect IL6-mediated MR activation of distal Na+ transporters, such as the sodium chloride cotransporter (NCC), a thiazide-sensitive Na+ uptake was performed on transwells in vehicle, IL6 (100ng/mL) or IL6-Gel (geldanamycin, HSP90 inhibitor; 5uM) in mDCT15 cells (n = 3). IL6 treatment increased Na+ uptake compared (1666 ± 12 nmol/mg/20 min vs.1449 ± 7; p < 0.001). With HSP90 inhibition, Na+ uptake was reduced (1499 ± 12; p < 0.001).

Conclusions:
Using RNA-seq, we have uncovered specific transcripts activated within the late distal nephron (DCT2) following IL6, including HSP90, which we confirmed to be an important and novel player in IL6-mediated activation of NCC.
IMMUNE CELLS MEDIATED EFFECTS OF SODIUM CHLORIDE ON THE DEVELOPMENT OF VASCULAR INFLAMMATION AND ABDOMINAL AORTIC ANEURYSM IN ANGIOTENSIN II-TREATED APOE-KO MICE
Authors: Stegbauer Johannes , Yakoub Mina , Rahman Masudur , Hering Lydia , Potthoff Sebastian , Argov Doron , Flögel Ulrich , Rump Lars Christian , Temme Sebastian 
Published: April 2021

Objective:
Chronic high salt (NaCl) intake is a major risk factor for cardiovascular diseases. Recent studies showed that excessive chronic NaCl intake affects immune response and thereby contributes to the pathogenesis of vascular injury. However, it remains unclear whether NaCl intake initially primes immune cell response by promoting memory T cells and sensitize the development of vascular injury in response to a subsequent stimulus.

Design and method:
Therefore, we investigate whether 14 days of NaCl treatment (1% NaCl) followed by a 7 day washout period affects the incidence and outcome of abdominal aortic aneurysms (AAA) in apolipoprotein E deficient (ApoE-KO) mice infused chronically with angiotensinII (AngII) (1000ng/kg/min) via osmotic minipumps for 10 days. Assessment of AAA was done by magnetic resonance imaging (MRI). To visualize vascular inflammation in vivo, perfluorocarbon nano-emulsions (PFC) injected intravenously before and 2, 4, 7 and 10 days after chronic AngII infusion were detected by combining 1H/19F MRI using a 19F RARE sequence. After 10 days of AngII infusion, aortas with perivascular fat were dissected. Aortic inflammation and immune cells infiltration were analyzed by flow cytometery, immunohistology and realtime PCR.

Results:
The survival rate of ApoE-KO mice pretreated with NaCl was significantly lower and the AAA incidence rate was significantly higher compared to sham-treated apoE-KO mice. The amount of 19F signal detected in areas of AAA was significantly increased in apoE-KO mice pretreated with NaCl. Histological analysis confirmed these results and showed that most of the immune cells were in the PVAT rather than dwelling in the vascular tissues. At day 10, proinflammatory cytokines like TNF-alpha, iNOS and TGF-ß as well as numbers of neutrophils, monocytes, effector memory CD4 and CD8 T cells were significantly higher in aortas of NaCl pretreated apoE-KO mice compared to sham-treated mice. Moreover, NaCl augmented the development of effector Th1 CD4 and effector CD8 cells from naïve T cells in vitro, respectively.

Conclusions:
In conclusion, these results suggest a significant role of NaCl in priming immune cell phenotype and thereby mediating vascular inflammation and damage in AngII infused apoE-KO mice.