Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 19.856
Filtrar
1.
Sci Rep ; 12(1): 20117, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36418458

RESUMO

SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.


Assuntos
COVID-19 , Hormônios Peptídicos , Humanos , Enzima de Conversão de Angiotensina 2 , Sistema Renina-Angiotensina , Angiotensina I , Angiotensina II , SARS-CoV-2 , Renina , Anti-Hipertensivos
2.
Vnitr Lek ; 68(7): 420-424, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36402565

RESUMO

From a certain stage, chronic kidney disease progresses to terminal kidney failure that requires renal replacement therapy with dialysis or transplantation. The progression can be significantly slowed by blocking the renin angiotensin aldosterone system (RAAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARB). Another new option to enhance the effect of blocking the RAAS system is the use of sodium glucose cotransporter 2 (SGLT2) inhibitors, or gliflozins. Dapagliflozin is currently available and reimbursed for patients with both diabetic and non-diabetic kidney disease. In the near future, treatment with the mineralocorticoid receptor inhibitor finerenone should be made available that significantly potentiates the effect of ACE or ARB inhibitors. Recent data show that it is possible to influence the progression of renal insufficiency with exercise.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Insuficiência Renal Crônica , Humanos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Sistema Renina-Angiotensina , Antagonistas de Receptores de Mineralocorticoides/farmacologia
3.
Cells ; 11(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36359814

RESUMO

Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, we hypothesize that tissue renin-angiotensin system (tRAS) components, including the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), are present in human nucleus pulposus (NP) cells and associated with inflammatory and degenerative processes. Experiments were performed with NP cells from four human donors. The existence of angiotensin II, angiotensin II type 1 receptor (AGTR1), AGTR2, MAS-receptor (MasR), and ACE2 in human NP cells was validated with immunofluorescent staining and gene expression analysis. Hereafter, the cell viability was assessed after adding agonists and antagonists of the target receptors as well as angiotensin II in different concentrations for up to 48 h of exposure. A TNF-α-induced inflammatory in vitro model was employed to assess the impact of angiotensin II addition and the stimulation or inhibition of the tRAS receptors on inflammation, tissue remodeling, expression of tRAS markers, and the release of nitric oxide (NO) into the medium. Furthermore, protein levels of IL-6, IL-8, IL-10, and intracellular as well as secreted angiotensin II were assessed after exposing the cells to the substances, and inducible nitric oxide synthase (iNOS) levels were evaluated by utilizing Western blot. The existence of tRAS receptors and angiotensin II were validated in human NP cells. The addition of angiotensin II only showed a mild impact on gene expression markers. However, there was a significant increase in NO secreted by the cells. The gene expression ratios of pro-inflammatory/anti-inflammatory cytokines IL-6/IL-10, IL-8/IL-10, and TNF-α/IL-10 were positively correlated with the AGTR1/AGTR2 and AGTR1/MAS1 ratios, respectively. The stimulation of the AGTR2 MAS-receptor and the inhibition of the AGTR1 receptor revealed beneficial effects on the gene expression of inflammatory and tissue remodeling markers. This finding was also present at the protein level. The current data showed that tRAS components are expressed in human NP cells and are associated with inflammatory and degenerative processes. Further characterization of the associated pathways is warranted. The findings indicate that tRAS modulation might be a novel therapeutic approach to intervertebral disc disease.


Assuntos
Núcleo Pulposo , Sistema Renina-Angiotensina , Humanos , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Núcleo Pulposo/citologia , Núcleo Pulposo/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Clin Sci (Lond) ; 136(21): 1513-1533, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36326719

RESUMO

For years, the AT2R-selective ligand CGP42112 has been erroneously characterized as a partial agonist, partly due to its ability to also interact with the AT1R at high concentrations. As late as 2009, it was still being characterized as an antagonist as well. In this perspective/opinion piece, we try to resolve the ambiguity that surrounds the efficacy of this compound by extensively reviewing the literature, tracing its beginnings to 1989, showing that CGP42112 has never been convincingly shown to be a partial agonist or an antagonist at the AT2R. While CGP42112 is now routinely characterized as an AT2R agonist, regrettably, there is a paucity of studies that can validate its efficacy as a full agonist at the AT2R, leaving the door open for continuing speculation regarding the extent of its efficacy. Hopefully, the information presented in this perspective/opinion piece will firmly establish CGP42112 as a full agonist at the AT2R such that it can once again be used as a tool to study the AT2R.


Assuntos
Receptor Tipo 2 de Angiotensina , Sistema Renina-Angiotensina , Receptor Tipo 2 de Angiotensina/agonistas , Oligopeptídeos , Ligantes
5.
Int J Mol Sci ; 23(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36361612

RESUMO

Treatments with sodium-glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin-angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.


Assuntos
Diabetes Mellitus Tipo 2 , Sistema Renina-Angiotensina , Camundongos , Animais , Transportador 2 de Glucose-Sódio , Atrasentana/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Glicemia , Ramipril/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptores de Endotelina
6.
Int J Mol Sci ; 23(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36430371

RESUMO

Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin-angiotensin-aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19's symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus.


Assuntos
COVID-19 , Sulfeto de Hidrogênio , Hipertensão , Humanos , Idoso , Sistema Renina-Angiotensina/fisiologia , Sulfeto de Hidrogênio/uso terapêutico , Óxido Nítrico , COVID-19/tratamento farmacológico , SARS-CoV-2 , Hipertensão/tratamento farmacológico
7.
BMJ ; 379: e072175, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384746

RESUMO

OBJECTIVE: To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. DESIGN: CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. SETTING: 17 hospital sites in India and Australia. PARTICIPANTS: Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. INTERVENTION: Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. MAIN OUTCOME MEASURES: The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. RESULTS: Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. CONCLUSIONS: In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. TRIAL REGISTRATION: ClinicalTrials.gov NCT04394117.


Assuntos
Antagonistas de Receptores de Angiotensina , COVID-19 , Humanos , Adolescente , Antagonistas de Receptores de Angiotensina/uso terapêutico , Telmisartan/uso terapêutico , COVID-19/tratamento farmacológico , SARS-CoV-2 , Sistema Renina-Angiotensina
8.
Physiol Rep ; 10(22): e15512, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36397298

RESUMO

Previous studies suggested that ongoing treatment with renin-angiotensin-aldosterone system (RAAS) inhibitor drugs may alter the course of SARS-CoV-2 infection and promote the development of more severe forms of the disease. The authors conducted a comparative, observational study to retrospectively analyze data collected from 394 patients admitted to ICU due to SARS-CoV-2 pneumonia. The primary aim of the study was to establish an association between the use of RAAS inhibitor drugs and mortality in the ICU. The secondary aims of the study were to establish an association between the use of RAAS inhibitor drugs and clinical severity at ICU admission, the need for tracheal intubation, total days of mechanical ventilation, and the ICU length of stay. The authors found no statistically significant difference in ICU mortality between patients on RAAS inhibitor drugs at admission and those who were not (31.3% versus 26.2% mortality, p-value 0.3). However, the group of patients taking RAAS inhibitor drugs appeared to be more critical at ICU admission, and this difference became statistically significant in the subgroup of non-hypertensive patients. ICU mortality in the subgroup of non-hypertensive patients treated with RAAS inhibitor drugs also tended to be higher. Overexpression of the angiotensin-converting enzyme 2 (ACE2) in human cells, induced by RAAS inhibitor drugs, promotes viral entry-replication of SARS-CoV-2 and alters the basal balance of the RAAS, which may explain the findings observed in the present study. These phenomena may be amplified in non-hypertensive patients treated with RAAS inhibitor therapy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , COVID-19 , Sistema Renina-Angiotensina , Humanos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Prognóstico , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos , SARS-CoV-2 , Unidades de Terapia Intensiva , Hospitalização
9.
Biomed Pharmacother ; 156: 113961, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411667

RESUMO

This study investigated the impacts of enteral cholecalciferol and/or intravenous calcitriol administration on the balance of cluster of differentiation 4-positive T cell subsets, the renin-angiotensin system (RAS), and the severity of acute lung injury (ALI) in obese mice with sepsis. Mice were fed a high-fat diet and then cecal ligation and puncture (CLP) was performed. Obese mice were divided into four sepsis groups: without vitamin D (VD) (S), with oral cholecalciferol 1 d before CLP (G), with intravenous calcitriol 1 h after CLP (V), and with both cholecalciferol before and intravenous calcitriol after CLP (GV). Mice were euthanized after CLP. The V and GV groups showed higher blood T helper (Th)1/Th2 and lower Th17/T regulatory (Treg) ratios than did the S and G groups. In the lungs, The V group had the lowest nuclear factor-κB and interleukin-1ß gene expressions among all groups 24 h post-CLP. In parallel, gene expressions of angiotensin type 2 receptor (AT2R), angiotensin-converting enzyme 2 (ACE2), and Mas receptor (MasR) were highest in the V group compared to other groups. The protein levels of MasR in the GV group and the AT2R/AT1R ratio in the V group were higher than those in the G and/or S groups. All of the VD-treated groups had lower injury scores than the S group. These findings suggest that calcitriol administration had more-pronounced impacts on regulating the homeostasis of Th/Treg cells and is prone to RAS-associated anti-inflammatory pathway in the lungs. However, both forms of VD attenuated sepsis-induced ALI in obese animals.


Assuntos
Lesão Pulmonar Aguda , Linfócitos T CD4-Positivos , Sepse , Animais , Camundongos , Lesão Pulmonar Aguda/complicações , Calcitriol/farmacologia , Homeostase , Camundongos Obesos , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Vitamina D/farmacologia , Vitaminas , Linfócitos T CD4-Positivos/imunologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-36320442

RESUMO

Renal ischemia-reperfusion injury (RIRI) is a sequence of complicated events that is defined as a reduction of the blood supply followed by reperfusion. RIRI is the leading cause of acute kidney injury (AKI). Among the diverse mediators that take part in RIRI-induced AKI, the renin-angiotensin system (RAS) plays an important role via conventional (angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT1R)) and nonconventional (ACE2, Ang 1-7, Ang 1-9, AT2 receptor (AT2R), and Mas receptor (MasR)) axes. RIRI alters the balance of both axes so that RAS can affect RIRI-induced AKI. In overall, the alteration of Ang II/AT1R and AKI by RIRI is important to consider. This review has looked for the effects and interactions of RAS activities during RIRI conditions.


Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Humanos , Sistema Renina-Angiotensina , Enzima de Conversão de Angiotensina 2 , Peptidil Dipeptidase A/metabolismo , Rim/metabolismo , Angiotensina II/metabolismo , Traumatismo por Reperfusão/metabolismo
11.
Nutrients ; 14(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36364864

RESUMO

This study aimed to identify the no-observed-adverse-effect level (NOAEL) of dietary epigallocatechin gallate (EGCG) supplementation and its possible antihypertensive and nutrigenomics effects in modulating intrarenal renin-angiotensin system (RAS) gene expression in spontaneously hypertensive rats (SHR). EGCG (50, 250, 500 or 1000 mg/kg b.w. i.g., once daily) was administered to SHR for 28 days. All the SHR survived with no signs of systemic toxicity. Increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and thiobarbituric acid reactive substances (TBARS) were evident in SHR supplemented with 500 and 1000 mg/kg b.w. but not in those supplemented with lower doses of EGCG. Subsequently, the NOAEL of EGCG was established at 250 mg/kg b.w., and the same protocol was replicated to assess its effects on blood pressure and renal RAS-related genes in SHR. The systolic blood pressure (SBP) of the EGCG group was consistently lower than the control group. The mRNA levels of cortical Agtr2 and Ace2 and medullary Agtr2, Ace and Mas1 were upregulated while medullary Ren was downregulated in EGCG group. Statistical analysis showed that SBP reduction was associated with the changes in medullary Agtr2, Ace, and Ren. Dietary EGCG supplementation exhibits antihypertensive and nutrigenomics effects through activation of intrarenal Ace and Agtr2 and suppression of Ren mediators, while a high dose of EGCG induced liver damage in SHR. In future clinical studies, liver damage biomarkers should be closely monitored to further establish the safety of the long-term use of EGCG.


Assuntos
Hipertensão , Sistema Renina-Angiotensina , Ratos , Animais , Ratos Endogâmicos SHR , Anti-Hipertensivos/farmacologia , Hipertensão/metabolismo , Pressão Sanguínea , Suplementos Nutricionais
12.
Nutrients ; 14(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364890

RESUMO

Hyperkalemia is associated with increased risks of mortality and adverse clinical outcomes. The treatment of hyperkalemia often leads to the discontinuation or restriction of beneficial but potassium-increasing therapy such as renin-angiotensin-aldosterone inhibitors (RAASi) and high-potassium diet including fruits and vegetables. To date, limited evidence is available for personalized risk evaluation in this heterogeneous and multifactorial pathophysiological condition. We developed risk prediction models using extreme gradient boosting (XGB), multiple logistic regression (LR), and deep neural network. Models were derived from a retrospective cohort of hyperkalemic patients with either heart failure or chronic kidney disease stage ≥3a from a Japanese nationwide database (1 April 2008-30 September 2018). Studied outcomes included all-cause death, renal replacement therapy introduction (RRT), hospitalization for heart failure (HHF), and cardiovascular events within three years after hyperkalemic episodes. The best performing model was further validated using an external cohort. A total of 24,949 adult hyperkalemic patients were selected for model derivation and internal validation. A total of 1452 deaths (16.6%), 887 RRT (10.1%), 1,345 HHF (15.4%), and 621 cardiovascular events (7.1%) were observed. XGB outperformed other models. The area under receiver operator characteristic curves (AUROCs) of XGB vs. LR (95% CIs) for death, RRT, HHF, and cardiovascular events were 0.823 (0.805-0.841) vs. 0.809 (0.791-0.828), 0.957 (0.947-0.967) vs. 0.947 (0.936-0.959), 0.863 (0.846-0.880) vs. 0.838 (0.820-0.856), and 0.809 (0.784-0.834) vs. 0.798 (0.772-0.823), respectively. In the external dataset including 86,279 patients, AUROCs (95% CIs) for XGB were: death, 0.747 (0.742-0.753); RRT, 0.888 (0.882-0.894); HHF, 0.673 (0.666-0.679); and cardiovascular events, 0.585 (0.578-0.591). Kaplan-Meier curves of the high-risk predicted group showed a statistically significant difference from that of the low-risk predicted groups for all outcomes (p < 0.005; log-rank test). These findings suggest possible use of machine learning models for real-world risk assessment as a guide for observation and/or treatment decision making that may potentially lead to improved outcomes in hyperkalemic patients while retaining the benefit of life-saving therapies.


Assuntos
Insuficiência Cardíaca , Hiperpotassemia , Adulto , Humanos , Hiperpotassemia/complicações , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Sistema Renina-Angiotensina , Estudos Retrospectivos , Potássio/farmacologia , Insuficiência Cardíaca/complicações , Anti-Hipertensivos/farmacologia , Aprendizado de Máquina
13.
Can Respir J ; 2022: 8698825, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36199292

RESUMO

Two and a half years after COVID-19 was first reported in China, thousands of people are still dying from the disease every day around the world. The condition is forcing physicians to adopt new treatment strategies while emphasizing continuation of vaccination programs. The renin-angiotensin system plays an important role in the development and progression of COVID-19 patients. Nonetheless, administration of recombinant angiotensin-converting enzyme 2 has been proposed for the treatment of the disease. The catalytic activity of cellular ACE2 (cACE2) and soluble ACE2 (sACE2) prevents angiotensin II and Des-Arg-bradykinin from accumulating in the body. On the other hand, SARS-CoV-2 mainly enters cells via cACE2. Thus, inhibition of ACE2 can prevent viral entry and reduce viral replication in host cells. The benefits of bradykinin inhibitors (BKs) have been reported in some COVID-19 clinical trials. Furthermore, the effects of cyclooxygenase (COX) inhibitors on ACE2 cleavage and prevention of viral entry into host cells have been reported in COVID-19 patients. However, the administration of COX inhibitors can reduce innate immune responses and have the opposite effect. A few studies suggest benefits of low-dose radiation therapy (LDR) in treating acute respiratory distress syndrome in COVID-19 patients. Nonetheless, radiation therapy can stimulate inflammatory pathways, resulting in adverse effects on lung injury in these patients. Overall, progress is being made in treating COVID-19 patients, but questions remain about which drugs will work and when. This review summarizes studies on the effects of a recombinant ACE2, BK and COX inhibitor, and LDR in patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Bradicinina/metabolismo , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Humanos , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/uso terapêutico , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandina-Endoperóxido Sintases/farmacologia , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2
15.
Front Immunol ; 13: 1002375, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36203608

RESUMO

The Endoplasmic Reticulum Aminopeptidase 1 and 2 (ERAP1 and ERAP2) and Insulin Regulated Aminopeptidase (IRAP) are three M1 zinc metalloproteases whose role in antigen processing is the refining of peptidome either in the Endoplasmic reticulum (ERAP1 and ERAP2), or in the endosomes (IRAP). However, other novel and distinct functions are emerging. Here, we focus specifically on ERAP2. This gene has a peculiar evolutionary history, being absent in rodents and undergoing in humans to a balanced selection of two haplotypes, one of which not expressing the full length ERAP2. These observations suggest that its role in antigen presentation is not essential. An additional, less investigated role is in the regulation of the Renin Angiotensin System (RAS). ERAP1 and ERAP2 cleave Angiotensin II (Ang II) into Ang III and IV, which counteract the action of Ang II whereas IRAP is itself the receptor for Ang IV. We have recently reported that macrophages, independently from the haplotype, express and release a N-terminus ERAP2 "short" form which directly binds IRAP and the two molecules are co-expressed in the endosomes and on the cell membrane. This new evidence suggests that the maintenance of the ERAP2 gene in humans could be due to its activity in the regulation of the RAS system, possibly as an Ang IV agonist. Its role in the immune-mediated diseases as well as in disorders more specifically related to an imbalance of the RAS system, including hypertension, pre-eclampsia but also viral infections such as COVID-19, is discussed here.


Assuntos
Aminopeptidases , COVID-19 , Angiotensina II/metabolismo , Apresentação de Antígeno , Humanos , Insulina/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Sistema Renina-Angiotensina/genética , Zinco
16.
Front Immunol ; 13: 963357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189295

RESUMO

The ACE2 receptors essential for SARS-CoV-2 infections are expressed not only in the lung but also in many other tissues in the human body. To better understand the disease mechanisms and progression, it is essential to understand how the virus affects and alters molecular pathways in the different affected tissues. In this study, we mapped the proteomics data obtained from Nie X. et al. (2021) to the pathway models of the COVID-19 Disease Map project and WikiPathways. The differences in pathway activities between COVID-19 and non-COVID-19 patients were calculated using the Wilcoxon test. As a result, 46% (5,235) of the detected proteins were found to be present in at least one pathway. Only a few pathways were altered in multiple tissues. As an example, the Kinin-Kallikrein pathway, an important inflammation regulatory pathway, was found to be less active in the lung, spleen, testis, and thyroid. We can confirm previously reported changes in COVID-19 patients such as the change in cholesterol, linolenic acid, and arachidonic acid metabolism, complement, and coagulation pathways in most tissues. Of all the tissues, we found the thyroid to be the organ with the most changed pathways. In this tissue, lipid pathways, energy pathways, and many COVID-19 specific pathways such as RAS and bradykinin pathways, thrombosis, and anticoagulation have altered activities in COVID-19 patients. Concluding, our results highlight the systemic nature of COVID-19 and the effect on other tissues besides the lung.


Assuntos
COVID-19 , Enzima de Conversão de Angiotensina 2 , Anticoagulantes , Ácido Araquidônico , Bradicinina/metabolismo , Humanos , Calicreínas/metabolismo , Masculino , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , Estudos Retrospectivos , SARS-CoV-2 , Ácido alfa-Linolênico
17.
Res Vet Sci ; 152: 564-568, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36183613

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is an enzyme within the renin-angiotensin-aldosterone system that plays a role in regulating blood pressure. However, it is also a cellular receptor for infection with SARS coronaviruses. Although most cats develop subclinical or mild disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) acquired from human patients, a previous study has suggested hypertrophic cardiomyopathy (HCM) is a potential risk factor for the development of severe disease in the cat. Herein we investigate the ACE2 protein expression in the lung, heart, and kidney from a small subset of cats with (n = 10) and without HCM (n = 10) by immunohistochemistry. The abundance and intensity of ACE2 expression is slightly elevated in alveoli (p = 0.09; 0.07, respectively) and bronchioles (p = 0.095; 0.37, respectively). However, statistically elevated abundance and intensity of ACE-2 expression was only evident in the heart of cats with HCM (p = 0.032; p = 0.011, respectively). Further investigation did not demonstrate a statistical correlation between the ACE2 expression in the heart in relation to the heart weight to body weight ratio, and the ventricular wall ratio. Current findings suggest an overexpression of ACE2 in HCM cases but follow up study is warranted to understand the pathophysiological process.


Assuntos
COVID-19 , Cardiomiopatia Hipertrófica , Doenças do Gato , Humanos , Gatos , Animais , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2 , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Seguimentos , COVID-19/veterinária , Sistema Renina-Angiotensina , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/veterinária , Cardiomiopatia Hipertrófica/metabolismo
18.
Biomolecules ; 12(10)2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36291638

RESUMO

Brain neurodegenerative diseases (BND) are debilitating conditions that are especially characteristic of a certain period of life and considered major threats to human health. Current treatments are limited, meaning that there is a challenge in developing new options that can efficiently tackle the different components and pathophysiological processes of these conditions. The renin-angiotensin-aldosterone system (RAS) is an endocrine axis with important peripheral physiological functions such as blood pressure and cardiovascular homeostasis, as well as water and sodium balance and systemic vascular resistance-functions which are well-documented. However, recent work has highlighted the paracrine and autocrine functions of RAS in different tissues, including the central nervous system (CNS). It is known that RAS hyperactivation has pro-inflammatory and pro-oxidant effects, thus suggesting that its pharmacological modulation could be used in the management of these conditions. The present paper underlines the involvement of RAS and its components in the pathophysiology of BNDs such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), motor neuron disease (MND), and prion disease (PRD), as well as the identification of drugs and pharmacologically active substances that act upon RAS, which could alleviate their symptomatology or evolution, and thus, contribute to novel therapeutic approaches.


Assuntos
Doenças Neurodegenerativas , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiologia , Doenças Neurodegenerativas/tratamento farmacológico , Espécies Reativas de Oxigênio , Sódio , Água/farmacologia
19.
Medicine (Baltimore) ; 101(42): e30846, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36281078

RESUMO

In the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mildly reduced left ventricular ejection fraction (EF) (41%-49%) have been increasing. This observational study aimed to investigate the association between the medical therapy with oral beta-blockers or inhibitors of renin-angiotensin system (RAS) and 2-year clinical outcomes in patients with mildly reduced EF after AMI. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health, propensity-score matched patients who survived the initial attack and had mildly reduced EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Beta-blocker therapy at discharge was associated with lower 2-year major adverse cardiac events which was a composite of cardiac death, myocardial infarction, revascularization and re-hospitalization due to heart failure (8.7 vs 12.8/100 patient-years; hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.50-0.93; P = .015), and no significant interaction between EF ≤ 45% and > 45% was observed (Pinteraction = 0.354). This association was mainly driven by lower myocardial infarction in patients with beta-blockers (HR 0.50; 95% CI 0.26-0.95; P = .035). Inhibitors of RAS at discharge were associated with lower re-hospitalization due to heart failure (1.8 vs 3.5/100 patient-years; HR 0.53; 95% CI 0.33-0.86; P = .010) without a significant interaction between EF ≤ 45% and > 45% (Pinteraction = 0.333). In patients with mildly reduced EF after AMI, the medical therapy with beta-blockers or RAS inhibitors at discharge was associated with better 2-year clinical outcomes.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Disfunção Ventricular Esquerda , Humanos , Volume Sistólico , Sistema Renina-Angiotensina , Função Ventricular Esquerda , Antagonistas Adrenérgicos beta/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico
20.
Eur J Pharmacol ; 936: 175344, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36270538

RESUMO

Weaning preeclamptic (PE) rats exhibit exaggerated endotoxic signs of hypotension and cardiac autonomic neuropathy. Considering the role of renin-angiotensin system (RAS) in maternal programming during PE, we investigated the hypothesis that gestational modulation of offensive (Angiotensin II, Ang II) and defensive (Ang 1-7) components of RAS alleviates cardiovascular hyperresponsiveness of weaning PE mothers to postpartum endotoxemia. PE was induced by treating pregnant rats with the nitric oxide synthase inhibitor L-NAME (50 mg/kg/day) for 7 consecutive days starting from gestational day 14. The PE-associated elevations in gestational systolic blood pressure and proteinuria were reduced after gestational treatment with Ang 1-7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, with the latter therapy being the most effective. In weaning PE rats, the potentiated falls in mean arterial pressure and spectral index of cardiac sympathovagal balance (low frequency/high frequency ratio) caused by i.v. Lipopolysaccharides (LPS, 5 mg/kg) were attenuated by all therapies. Pioglitazone and Ang 1-7 were more effective in reversing increases and decreases in left ventricular contractility and isovolumic relaxation time constant, respectively, seen in endotoxic PE mothers. Immunohistochemically, cardiac Toll-like receptor 4 (TLR-4) expression was increased in endotoxic PE rats, and this effect was abrogated by Ang 1-7 or losartan/pioglitazone. The same treatments blunted the increased cardiac angiotensin converting enzyme (ACE) expression whereas ACE2 expression was altered by none of the intervening therapies. Overall, the mitigation of Ang II/ACE imbalances alleviates the sensitized cardiovascular and inflammatory actions of endotoxemia in weaning PE mothers.


Assuntos
Endotoxemia , Pré-Eclâmpsia , Gravidez , Humanos , Feminino , Ratos , Animais , Losartan/farmacologia , Endotoxemia/induzido quimicamente , Endotoxemia/complicações , Desmame , Pioglitazona/farmacologia , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina , Angiotensina II/farmacologia , Pré-Eclâmpsia/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...