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  1 / 1953 MEDLINE  
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[PMID]:28461598
[Au] Autor:Mirabito Colafella KM; Danser AHJ
[Ad] Endereço:From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands (K.M.M.C., A.H.J.D.); and Cardiovascular Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Australia (K.M.M.C.).
[Ti] Título:Recent Advances in Angiotensin Research.
[So] Source:Hypertension;69(6):994-999, 2017 06.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Angiotensinas/metabolismo
Encéfalo/metabolismo
Hipertensão/metabolismo
Rim/metabolismo
Receptores de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Masculino
Gravidez
Sistema Renina-Angiotensina/fisiologia
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Angiotensins); 0 (Receptors, Angiotensin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.08931


  2 / 1953 MEDLINE  
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[PMID]:29223539
[Au] Autor:Atanasova D; Tchekalarova J; Ivanova N; Nenchovska Z; Pavlova E; Atanassova N; Lazarov N
[Ad] Endereço:Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria; Department of Anatomy, Faculty of Medicine, Trakia University, Stara Zagora 6003, Bulgaria; Department of Genes and Behavior, Max Planck Institute of Biophysical Chemistry, Göttingen 37077, Germany. Electronic address: d
[Ti] Título:Losartan suppresses the kainate-induced changes of angiotensin AT receptor expression in a model of comorbid hypertension and epilepsy.
[So] Source:Life Sci;193:40-46, 2018 Jan 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Experimental and clinical studies have demonstrated that components of renin-angiotensin system are elevated in the hippocampus in epileptogenic conditions. In the present work, we explored the changes in the expression of angiotensin II receptor, type 1 (AT receptor) in limbic structures, as well as the effect of the AT1 receptor antagonist losartan in a model of comorbid hypertension and epilepsy. MAIN METHODS: The expression of AT receptors was compared between spontaneously hypertensive rats (SHRs) and Wistar rats by using immunohistochemistry in the kainate (KA) model of temporal lobe epilepsy (TLE). The effect of losartan was studied on AT receptor expression in epileptic rats that were treated for a period of 4weeks after status epilepticus. KEY FINDINGS: The naive and epileptic SHRs were characterized by stronger protein expression of AT receptor than normotensive Wistar rats in the CA1, CA3a, CA3b, CA3c field and the hilus of the dentate gyrus of the dorsal hippocampus but fewer cells were immunostained in the piriform cortex. Increased AT immunostaining was observed in the basolateral amygdala of epileptic SHRs but not of epileptic Wistar rats. Losartan exerted stronger and structure-dependent suppression of AT receptor expression in SHRs compared to Wistar rats. SIGNIFICANCE: Our results confirm the important role of AT receptor in epilepsy and suggest that the AT receptor antagonists could be used as a therapeutic strategy for treatment of comorbid hypertension and epilepsy.
[Mh] Termos MeSH primário: Losartan/farmacologia
Receptor Tipo 1 de Angiotensina/efeitos dos fármacos
[Mh] Termos MeSH secundário: Angiotensina II/farmacologia
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia
Angiotensinas
Animais
Pressão Sanguínea/efeitos dos fármacos
Comorbidade
Modelos Animais de Doenças
Epilepsia/tratamento farmacológico
Expressão Gênica/efeitos dos fármacos
Hipocampo/metabolismo
Hipertensão/tratamento farmacológico
Ácido Caínico/efeitos adversos
Ácido Caínico/metabolismo
Sistema Límbico/patologia
Losartan/metabolismo
Losartan/uso terapêutico
Masculino
Ratos
Ratos Endogâmicos SHR
Ratos Wistar
Sistema Renina-Angiotensina/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin II Type 1 Receptor Blockers); 0 (Angiotensins); 0 (Receptor, Angiotensin, Type 1); 11128-99-7 (Angiotensin II); JMS50MPO89 (Losartan); SIV03811UC (Kainic Acid)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171211
[St] Status:MEDLINE


  3 / 1953 MEDLINE  
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[PMID]:28559246
[Au] Autor:Brar GS; Barrow BM; Watson M; Griesbach R; Choung E; Welch A; Ruzsicska B; Raleigh DP; Zraika S
[Ad] Endereço:Veterans Affairs Puget Sound Health Care System, Seattle, WA.
[Ti] Título:Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2).
[So] Source:Diabetes;66(8):2201-2212, 2017 Aug.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve ß-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1-7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1-7) and neprilysin-derived degradation products angiotensin-(1-4), angiotensin-(5-7), and angiotensin-(3-4) failed to enhance GSIS. Conversely, angiotensin-(1-2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein-coupled receptor (GPCR) MasR, angiotensin-(1-2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1-7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1-7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1-7) compounds and neprilysin inhibitors as therapies for diabetes.
[Mh] Termos MeSH primário: Angiotensina I/fisiologia
Angiotensinas/metabolismo
Insulina/secreção
Neprilisina/deficiência
Fragmentos de Peptídeos/fisiologia
Sistema Renina-Angiotensina/fisiologia
[Mh] Termos MeSH secundário: Animais
Glucose/fisiologia
Células Secretoras de Insulina/enzimologia
Células Secretoras de Insulina/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Neprilisina/fisiologia
Peptidil Dipeptidase A/metabolismo
Proteólise
Receptores Acoplados a Proteínas-G/fisiologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensins); 0 (Insulin); 0 (Peptide Fragments); 0 (Receptors, G-Protein-Coupled); 9041-90-1 (Angiotensin I); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2); EC 3.4.24.11 (Neprilysin); IJ3FUK8MOF (angiotensin I (1-7)); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.2337/db16-1318


  4 / 1953 MEDLINE  
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[PMID]:28390678
[Au] Autor:Goh SS; Sia CH; Ngiam NJ; Tan BY; Lee PS; Tay EL; Kong WK; Yeo TC; Poh KK
[Ad] Endereço:Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
[Ti] Título:Effect of Renin-Angiotensin Blockers on Left Ventricular Remodeling in Severe Aortic Stenosis.
[So] Source:Am J Cardiol;119(11):1839-1845, 2017 Jun 01.
[Is] ISSN:1879-1913
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Studies have shown that medical therapy with renin-angiotensin blockers (RABs) may benefit patients with aortic stenosis (AS). However, its use and efficacy remains controversial, including in patients with low flow (LF) with preserved left ventricular ejection fraction (LVEF). We examined the effects of RAB use on LV remodeling in patients with severe AS with preserved LVEF, analyzing the differential effects in patients with LF compared with normal flow (NF). This is a retrospective study of 428 consecutive subjects from 2005 to 2014 with echocardiographic diagnosis of severe AS and preserved LVEF. Clinical and echocardiographic parameters were systematically collected and analyzed. Two hundred forty-two (57%) patients had LF. Sixty-four LF patients (26%) were treated with RAB. Patients on RAB treatment had a higher incidence of hyperlipidemia (69% vs 44%) and diabetes mellitus (53% vs 34%). Severity of AS in terms of valve area, transvalvular mean pressure gradient, and aortic valve resistance were similar between both groups as was the degree of LV diastolic function. The RAB group demonstrated significantly lower LV mass index with a correspondingly lower incidence of concentric LV hypertrophy. Regardless of the duration of RAB therapy, patients had increased odds of having a preserved LV mass index compared with those without RAB therapy. In conclusion, RAB therapy may be associated with less LV pathological remodeling and have a role in delaying patients from developing cardiovascular complications of AS.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Angiotensina/uso terapêutico
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico
Estenose da Valva Aórtica/tratamento farmacológico
Ventrículos do Coração/fisiopatologia
Volume Sistólico/fisiologia
Função Ventricular Esquerda/fisiologia
Remodelação Ventricular/efeitos dos fármacos
[Mh] Termos MeSH secundário: Idoso
Angiotensinas/antagonistas & inibidores
Estenose da Valva Aórtica/diagnóstico
Estenose da Valva Aórtica/fisiopatologia
Progressão da Doença
Ecocardiografia Doppler
Feminino
Ventrículos do Coração/diagnóstico por imagem
Seres Humanos
Masculino
Renina/antagonistas & inibidores
Estudos Retrospectivos
Índice de Gravidade de Doença
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin Receptor Antagonists); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Angiotensins); EC 3.4.23.15 (Renin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170410
[St] Status:MEDLINE


  5 / 1953 MEDLINE  
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[PMID]:28287881
[Au] Autor:Sedláková L; Certíková Chábová V; Dolezelová S; Skaroupková P; Kopkan L; Husková Z; Cervenková L; Kikerlová S; Vanecková I; Sadowski J; Kompanowska-Jezierska E; Kujal P; Kramer HJ; Cervenka L
[Ad] Endereço:a Center for Experimental Medicine, Institute for Clinical and Experimental Medicine , Prague , Czech Republic.
[Ti] Título:Renin-angiotensin system blockade alone or combined with ET receptor blockade: effects on the course of chronic kidney disease in 5/6 nephrectomized Ren-2 transgenic hypertensive rats.
[So] Source:Clin Exp Hypertens;39(2):183-195, 2017.
[Is] ISSN:1525-6006
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Early addition of endothelin (ET) type A (ET ) receptor blockade to complex renin-angiotensin system (RAS) blockade has previously been shown to provide better renoprotection against progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). In this study, we examined if additional protection is provided when ET blockade is applied in rats with already developed CKD. METHODS: For complex RAS inhibition, an angiotensin-converting enzyme inhibitor along with angiotensin II type 1 receptor blocker was used. Alternatively, ET receptor blocker was added to the RAS blockade. The treatments were initiated 6 weeks after 5/6 NX and the follow-up period was 50 weeks. RESULTS: When applied in established CKD, addition of ET receptor blockade to the complex RAS blockade brought no further improvement of the survival rate (30% in both groups); surprisingly, aggravated albuminuria (588 ± 47 vs. 245 ± 38 mg/24 h, p < 0.05) did not reduce renal glomerular injury index (1.25 ± 0.29 vs. 1.44 ± 0.26), did not prevent the decrease in creatinine clearance (203 ± 21 vs. 253 ± 17 µl/min/100 g body weight), and did not attenuate cardiac hypertrophy to a greater extent than observed in 5/6 NX TGR treated with complex RAS blockade alone. CONCLUSIONS: When applied in the advanced phase of CKD, addition of ET receptor blockade to the complex RAS blockade brings no further beneficial renoprotective effects on the CKD progression in 5/6 NX TGR, in addition to those seen with RAS blockade alone.
[Mh] Termos MeSH primário: Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia
Inibidores da Enzima Conversora de Angiotensina/farmacologia
Pressão Sanguínea/efeitos dos fármacos
Antagonistas do Receptor de Endotelina A/farmacologia
Taxa de Filtração Glomerular/efeitos dos fármacos
Rim/efeitos dos fármacos
Insuficiência Renal Crônica/metabolismo
Sistema Renina-Angiotensina/efeitos dos fármacos
[Mh] Termos MeSH secundário: Albuminúria
Angiotensinas/efeitos dos fármacos
Angiotensinas/metabolismo
Animais
Cardiomegalia
Creatinina/metabolismo
Progressão da Doença
Quimioterapia Combinada
Hipertensão
Indóis/farmacologia
Rim/metabolismo
Losartan/farmacologia
Masculino
Nefrectomia
Pirrolidinas/farmacologia
Ratos
Ratos Sprague-Dawley
Ratos Transgênicos
Receptor de Endotelina A/efeitos dos fármacos
Receptor de Endotelina A/metabolismo
Receptor de Endotelina B/efeitos dos fármacos
Receptor de Endotelina B/metabolismo
Renina/efeitos dos fármacos
Renina/metabolismo
Taxa de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin II Type 1 Receptor Blockers); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Angiotensins); 0 (Endothelin A Receptor Antagonists); 0 (Indoles); 0 (Pyrrolidines); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 1T0N3G9CRC (trandolapril); AYI8EX34EU (Creatinine); EC 3.4.23.15 (Renin); JMS50MPO89 (Losartan); V6D7VK2215 (atrasentan)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170314
[St] Status:MEDLINE
[do] DOI:10.1080/10641963.2016.1235184


  6 / 1953 MEDLINE  
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[PMID]:28209222
[Au] Autor:Basu R; Poglitsch M; Yogasundaram H; Thomas J; Rowe BH; Oudit GY
[Ad] Endereço:Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
[Ti] Título:Roles of Angiotensin Peptides and Recombinant Human ACE2 in Heart Failure.
[So] Source:J Am Coll Cardiol;69(7):805-819, 2017 Feb 21.
[Is] ISSN:1558-3597
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The renin-angiotensin system (RAS) is activated in heart failure (HF) and inhibition of RAS is a mainstay therapy for HF. Angiotensin-converting enzyme 2 (ACE2) and its product, angiotensin 1-7 (Ang-[1-7]), are important negative regulators of the RAS. OBJECTIVES: A comprehensive examination of angiotensin peptide levels and therapeutic effects of recombinant human ACE2 (rhACE2) on peptide metabolism was evaluated in human plasma and explanted heart tissue from patients with HF. METHODS: Using prospective cohorts with chronic (n = 59) and acute (n = 42) HF, plasma angiotensin analysis was performed using a unique liquid chromatography-mass spectrometry/mass spectroscopy method quantifying circulating and equilibrium levels. Angiotensin II (Ang II) metabolism was examined in human explanted hearts with dilated cardiomyopathy (n = 25). RESULTS: The dynamic range of the RAS was large, with equilibrium angiotensin levels being 8- to 10-fold higher compared with circulating angiotensin levels. In chronic HF patients receiving ACE inhibition, plasma Ang II was suppressed and plasma Ang-(1-7) was elevated, whereas acute HF and patients receiving angiotensin receptor blocker had higher plasma Ang II with lower Ang-(1-7) levels. Suppressed Ang-(1-7)/Ang II ratio was associated with worsening HF symptoms and longer hospitalization. Recombinant human ACE2 effectively metabolized Ang-(1-10) and Ang II into Ang-(1-9) and Ang-(1-7), respectively. Myocardial Ang II levels in explanted human hearts with dilated cardiomyopathy were elevated despite ACE inhibition with elevated chymase activity, and Ang II was effectively converted to Ang-(1-7) by rhACE2. CONCLUSIONS: Plasma angiotensin peptides represent a dynamic network that is altered in HF and in response to rhACE2. An increased plasma Ang-(1-7) level is linked to ACE inhibitor use, whereas acute HF reduced Ang-(1-7) levels and suppressed the Ang-(1-7)/Ang II ratio. Increased chymase activity elevated Ang II levels in failing human hearts. Use of rhACE2 effectively normalized elevated Ang II while increasing Ang-(1-7) and Ang-(1-9) levels.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Angiotensina/uso terapêutico
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico
Angiotensinas/fisiologia
Insuficiência Cardíaca/sangue
Insuficiência Cardíaca/terapia
[Mh] Termos MeSH secundário: Doença Aguda
Idoso
Idoso de 80 Anos ou mais
Estudos de Casos e Controles
Doença Crônica
Feminino
Insuficiência Cardíaca/complicações
Seres Humanos
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin Receptor Antagonists); 0 (Angiotensin-Converting Enzyme Inhibitors); 0 (Angiotensins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170218
[St] Status:MEDLINE


  7 / 1953 MEDLINE  
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[PMID]:28177279
[Au] Autor:Vallianou NG; Trigkidis K; Kazazis C
[Ti] Título:Sodium glucose co-transporter 2 inhibitors and their nephroprotective potential
.
[So] Source:Clin Nephrol;87 (2017)(4):212-216, 2017 Apr.
[Is] ISSN:0301-0430
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Chronic kidney disease among patients with diabetes is on the rise. The sodium glucose co-transporters 2 inhibitors are a new class of glucose-lowering agents, which act through a novel mechanism by producing a decline in glucose reabsorption in the kidney, thereby increasing glucosuria and decreasing serum glucose levels. Data suggest that they possess nephroprotective properties. It is noteworthy that the efferent glomerular arteriole is 10 - 100 times more sensitive to the vasoconstrictive properties of angiotensin II than the afferent one and this might account for the consequently higher intra-glomerular capillary pressure, which is believed to be the cornerstone of diabetic nephropathy. These drugs are demonstrated to restore intra-glomerular pressure by increasing angiotensin (1 - 7), which exerts vasodilatory and anti-inflammatory effects. In this review, the nephroprotective potential of this novel class of glucose-lowering drugs will be further discussed.
.
[Mh] Termos MeSH primário: Glicemia/metabolismo
Diabetes Mellitus Tipo 2/tratamento farmacológico
Nefropatias Diabéticas/metabolismo
Hipoglicemiantes/uso terapêutico
Glomérulos Renais/metabolismo
Substâncias Protetoras/uso terapêutico
Insuficiência Renal Crônica/metabolismo
Transportador 2 de Glucose-Sódio/antagonistas & inibidores
[Mh] Termos MeSH secundário: Angiotensinas/metabolismo
Compostos Benzidrílicos/uso terapêutico
Canagliflozina/uso terapêutico
Diabetes Mellitus Tipo 2/complicações
Nefropatias Diabéticas/etiologia
Glucosídeos/uso terapêutico
Seres Humanos
Rim/irrigação sanguínea
Rim/metabolismo
Glomérulos Renais/irrigação sanguínea
Insuficiência Renal Crônica/etiologia
Vasoconstrição
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol); 0 (Angiotensins); 0 (Benzhydryl Compounds); 0 (Blood Glucose); 0 (Glucosides); 0 (Hypoglycemic Agents); 0 (Protective Agents); 0 (Sodium-Glucose Transporter 2); 0SAC974Z85 (Canagliflozin); HDC1R2M35U (empagliflozin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.5414/CN109013


  8 / 1953 MEDLINE  
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[PMID]:28102934
[Au] Autor:Kanarek AM; Wagner A; Küppers J; Gütschow M; Postina R; Kojro E
[Ad] Endereço:Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
[Ti] Título:Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein.
[So] Source:FEBS J;284(5):742-753, 2017 Mar.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The association between hypertension and an increased risk for Alzheimer's disease (AD) and dementia is well established. Many data suggest that modulation of the renin-angiotensin system may be meaningful for the prevention and therapy of neurodegenerative disorders, in particular AD. Proteolytic cleavage of the amyloid precursor protein (APP) by α-secretase precludes formation of neurotoxic Aß peptides and is expected to counteract the development of AD. An established approach for the up-regulation of α-secretase cleavage is the activation of G protein-coupled receptors (GPCRs). Therefore, our study aimed to analyze whether stimulation of angiotensin AT or AT receptors stably expressed in HEK cells influence the nonamyloidogenic pathway of APP processing. Treatment of both receptors with angiotensin II clearly showed that only activation of the AT receptor increased several fold the α-secretase-mediated shedding of APP. This effect was completely abolished by treatment with the AT receptor-specific antagonist telmisartan. Using the BIM-46187 inhibitor, we demonstrate that the Gαq protein-mediated pathway is involved in this stimulation process. Stimulation of AT receptors with the ß-arrestin-biased agonist SII was ineffective regarding α-secretase-mediated APP shedding. This result discloses that only the G protein-dependent pathway is involved in the Ang II-induced APP shedding. Blocking of Gßγ subunits by the inhibitor gallein completely prevented constitutive and Ang II-induced APP shedding. Our findings provide evidence that induction of APP shedding via Ang II/AT receptor stimulation is effected by G protein activation with Gßγ subunits playing important roles.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Precursor de Proteína beta-Amiloide/genética
Angiotensinas/metabolismo
Receptor Tipo 1 de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Secretases da Proteína Precursora do Amiloide/genética
Secretases da Proteína Precursora do Amiloide/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Amiloidose/genética
Amiloidose/patologia
Angiotensinas/genética
Cicloexanos/administração & dosagem
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo
Subunidades beta da Proteína de Ligação ao GTP/genética
Subunidades beta da Proteína de Ligação ao GTP/metabolismo
Subunidades gama da Proteína de Ligação ao GTP/genética
Subunidades gama da Proteína de Ligação ao GTP/metabolismo
Células HEK293
Seres Humanos
Proteólise/efeitos dos fármacos
Pirazinas/administração & dosagem
Receptor Tipo 1 de Angiotensina/genética
Receptor Tipo 2 de Angiotensina/genética
Receptor Tipo 2 de Angiotensina/metabolismo
beta-Arrestinas/agonistas
beta-Arrestinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride); 0 (Amyloid beta-Protein Precursor); 0 (Angiotensins); 0 (Cyclohexanes); 0 (GTP-Binding Protein alpha Subunits); 0 (GTP-Binding Protein beta Subunits); 0 (GTP-Binding Protein gamma Subunits); 0 (Pyrazines); 0 (Receptor, Angiotensin, Type 1); 0 (Receptor, Angiotensin, Type 2); 0 (beta-Arrestins); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170120
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14015


  9 / 1953 MEDLINE  
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[PMID]:28096461
[Au] Autor:Young BM; Nguyen E; Chedrawe MA; Rainey JK; Dupré DJ
[Ad] Endereço:From the Departments of Pharmacology.
[Ti] Título:Differential Contribution of Transmembrane Domains IV, V, VI, and VII to Human Angiotensin II Type 1 Receptor Homomer Formation.
[So] Source:J Biol Chem;292(8):3341-3350, 2017 Feb 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:G protein-coupled receptors (GPCRs) play an important role in drug therapy and represent one of the largest families of drug targets. The angiotensin II type 1 receptor (AT1R) is notable as it has a central role in the treatment of cardiovascular disease. Blockade of AT1R signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. Despite this, it has become apparent that our initial understanding of AT1R signaling is oversimplified. There is considerable evidence to suggest that AT1R signaling is highly modified in the presence of receptor-receptor interactions, but there is very little structural data available to explain this phenomenon even with the recent elucidation of the AT1R crystal structure. The current study investigates the involvement of transmembrane domains in AT1R homomer assembly with the goal of identifying hydrophobic interfaces that contribute to receptor-receptor affinity. A recently published crystal structure of the AT1R was used to guide site-directed mutagenesis of outward-facing hydrophobic residues within the transmembrane region of the AT1R. Bioluminescence resonance energy transfer was employed to analyze how receptor mutation affects the assembly of AT1R homomers with a specific focus on hydrophobic residues. Mutations within transmembrane domains IV, V, VI, and VII had no effect on angiotensin-mediated ß-arrestin1 recruitment; however, they exhibited differential effects on the assembly of AT1R into oligomeric complexes. Our results demonstrate the importance of hydrophobic amino acids at the AT1R transmembrane interface and provide the first glimpse of the requirements for AT1R complex assembly.
[Mh] Termos MeSH primário: Receptor Tipo 1 de Angiotensina/química
Receptor Tipo 1 de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Angiotensinas/metabolismo
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Modelos Moleculares
Mutagênese Sítio-Dirigida
Domínios Proteicos
Multimerização Proteica
Receptor Tipo 1 de Angiotensina/genética
beta-Arrestinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensins); 0 (Receptor, Angiotensin, Type 1); 0 (beta-Arrestins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.750380


  10 / 1953 MEDLINE  
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[PMID]:28005703
[Au] Autor:Martini AG; Krop M; Saleh L; Garrelds IM; Danser AH
[Ad] Endereço:Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
[Ti] Título:Do prorenin-synthesizing cells release active, 'open' prorenin?
[So] Source:J Hypertens;35(2):330-337, 2017 Feb.
[Is] ISSN:1473-5598
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The function of prorenin, the inactive precursor of renin, remains unclear after many decades of research. The discovery of a (pro)renin receptor suggested that prorenin, by binding to this receptor, would become active, that is, obtain an 'open' conformation. However, the receptor only interacted with prorenin at levels that were many orders of magnitude above its normal levels, making such interaction in-vivo unlikely. Prorenin occurs in two conformations, an open, active form, and a closed, inactive form. Under physiological conditions (pH 7.4, 37 °C), virtually all prorenin occurs in the closed conformation. This study investigated to what degree prorenin-synthesizing cells release prorenin in an open conformation. METHODS AND RESULTS: Renin plus prorenin-synthesizing human mast cells, and prorenin-synthesizing HEK293 cells (transfected with the mammalian expression vector pRhR1100, containing human prorenin) and human decidua cells were incubated with the renin inhibitor VTP-27999. This inhibitor will trap open prorenin, as after VTP-27999 binding, prorenin can no longer return to its closed conformation, thus allowing its detection in a renin immunoradiometric assay. No evidence for the release of open prorenin was found. Moreover, incubating decidua cells with angiotensinogen yielded low angiotensin levels, corresponding with the activity of ≈1% of prorenin in the medium, that is, the amount of open prorenin expected based upon the equilibrium between open and closed prorenin under physiological conditions. CONCLUSION: Our study does not reveal evidence for the release of open, active prorenin by prorenin-synthesizing cells, at least under cell culture conditions. This argues against prorenin activity at the site of its release.
[Mh] Termos MeSH primário: Renina/biossíntese
Renina/química
[Mh] Termos MeSH secundário: Adulto
Angiotensinogênio/farmacologia
Angiotensinas/metabolismo
Anti-Hipertensivos
Carbamatos/farmacologia
Decídua/citologia
Decídua/efeitos dos fármacos
Decídua/secreção
Feminino
Células HEK293/efeitos dos fármacos
Células HEK293/secreção
Seres Humanos
Masculino
Mastócitos/efeitos dos fármacos
Mastócitos/secreção
Meia-Idade
Piperidinas/farmacologia
Renina/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensins); 0 (Antihypertensive Agents); 0 (Carbamates); 0 (Piperidines); 0 (methyl (2-((3-chlorophenyl)(1-((2-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propyl)carbamoyl)piperidin-3-yl)methoxy)ethyl)carbamate); 11002-13-4 (Angiotensinogen); EC 3.4.23.15 (Renin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1097/HJH.0000000000001174



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