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[PMID]:28744580
[Au] Autor:Wester A; Devocelle M; Tallant EA; Chappell MC; Gallagher PE; Paradisi F
[Ad] Endereço:School of Chemistry, University College Dublin, Dublin, Ireland.
[Ti] Título:Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.
[So] Source:Amino Acids;49(10):1733-1742, 2017 10.
[Is] ISSN:1438-2199
[Cp] País de publicação:Austria
[La] Idioma:eng
[Ab] Resumo:Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer.
[Mh] Termos MeSH primário: Substituição de Aminoácidos
Angiotensina I
Dipeptidil Peptidases e Tripeptidil Peptidases/química
Fragmentos de Peptídeos
Peptidil Dipeptidase A/química
Proteólise
[Mh] Termos MeSH secundário: Angiotensina I/síntese química
Angiotensina I/química
Seres Humanos
Fragmentos de Peptídeos/síntese química
Fragmentos de Peptídeos/química
Estabilidade Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Peptide Fragments); 9041-90-1 (Angiotensin I); EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases); EC 3.4.14.4 (DPP3 protein, human); EC 3.4.15.1 (Peptidyl-Dipeptidase A); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1007/s00726-017-2471-9


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[PMID]:29211853
[Au] Autor:Zhao S; Ghosh A; Lo CS; Chenier I; Scholey JW; Filep JG; Ingelfinger JR; Zhang SL; Chan JSD
[Ad] Endereço:Centre de Recherche, Centre Hospitalier de l'Université de Montréal and Département de Médecine, Université de Montréal, Montréal, Quebec, Canada.
[Ti] Título:Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice.
[So] Source:Endocrinology;159(2):836-852, 2018 02 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 in Akita mice attenuated hypertension, renal injury, tubulointerstitial fibrosis, and the urinary albumin/creatinine ratio. Furthermore, loss of Nrf2 upregulated RPTC Ace2 and MasR expression, increased urinary Ang 1-7 levels, and downregulated expression of Agt, ACE, and profibrotic genes in Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose stimulation of Nrf2 nuclear translocation, Agt, and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes.
[Mh] Termos MeSH primário: Nefropatias Diabéticas/genética
Hipertensão/genética
Rim/metabolismo
Fator 2 Relacionado a NF-E2/genética
Peptidil Dipeptidase A/genética
Receptor Tipo 2 de Angiotensina/genética
[Mh] Termos MeSH secundário: Angiotensina I/metabolismo
Animais
Células Cultivadas
Diabetes Mellitus Experimental/complicações
Diabetes Mellitus Experimental/genética
Diabetes Mellitus Experimental/metabolismo
Nefropatias Diabéticas/metabolismo
Nefropatias Diabéticas/patologia
Regulação Enzimológica da Expressão Gênica
Hipertensão/complicações
Hipertensão/metabolismo
Hipertensão/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Fragmentos de Peptídeos/metabolismo
Peptidil Dipeptidase A/metabolismo
Ratos
Receptor Tipo 2 de Angiotensina/metabolismo
Sistema Renina-Angiotensina/genética
Sistema Renina-Angiotensina/fisiologia
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Peptide Fragments); 0 (Receptor, Angiotensin, Type 2); 9041-90-1 (Angiotensin I); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00752


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[PMID]:29203630
[Au] Autor:Touyz RM; Montezano AC
[Ad] Endereço:From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom. rhian.touyz@glasgow.ac.uk.
[Ti] Título:Angiotensin-(1-7) and Vascular Function: The Clinical Context.
[So] Source:Hypertension;71(1):68-69, 2018 01.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Angiotensina I
Fragmentos de Peptídeos
[Mh] Termos MeSH secundário: Angiotensina II
Seres Humanos
Músculo Liso Vascular
[Pt] Tipo de publicação:EDITORIAL; RESEARCH SUPPORT, NON-U.S. GOV'T; COMMENT
[Nm] Nome de substância:
0 (Peptide Fragments); 11128-99-7 (Angiotensin II); 9041-90-1 (Angiotensin I); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.10406


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[PMID]:29296021
[Au] Autor:Li T; Yu B; Liu Z; Li J; Ma M; Wang Y; Zhu M; Yin H; Wang X; Fu Y; Yu F; Wang X; Fang X; Sun J; Kong W
[Ad] Endereço:Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China.
[Ti] Título:Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury.
[So] Source:Nat Commun;9(1):11, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg and Cys residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.
[Mh] Termos MeSH primário: Aneurisma da Aorta Abdominal/metabolismo
Homocisteína/metabolismo
Receptor Tipo 1 de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Angiotensina I/metabolismo
Angiotensina II/metabolismo
Animais
Células HEK293
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Simulação de Dinâmica Molecular
Mutagênese Sítio-Dirigida
Conformação Proteica
Lesões do Sistema Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptor, Angiotensin, Type 1); 0LVT1QZ0BA (Homocysteine); 11128-99-7 (Angiotensin II); 9041-90-1 (Angiotensin I)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02401-7


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[PMID]:29203627
[Au] Autor:Schinzari F; Tesauro M; Veneziani A; Mores N; Di Daniele N; Cardillo C
[Ad] Endereço:From the Policlinico A. Gemelli, Rome, Italy (F.S., A.V., N.M., C.C.); Department of Internal Medicine, University of Tor Vergata, Rome, Italy (M.T., N.D.D.); and Departments of Surgery (A.V.), Pharmacology (N.M.), and Internal Medicine (C.C.), Catholic University, Rome, Italy.
[Ti] Título:Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity.
[So] Source:Hypertension;71(1):185-191, 2018 01.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow ( =0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; >0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both >0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) ( =0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified ( =0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; <0.001); nitric oxide inhibition by l- -monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) ( =0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity.
[Mh] Termos MeSH primário: Angiotensina I/metabolismo
Endotelina-1/metabolismo
Insulina
Obesidade
Fragmentos de Peptídeos/metabolismo
Fluxo Sanguíneo Regional/efeitos dos fármacos
Vasoconstrição
Vasodilatação
[Mh] Termos MeSH secundário: Adulto
Feminino
Antebraço/irrigação sanguínea
Seres Humanos
Insulina/metabolismo
Insulina/farmacocinética
Masculino
Meia-Idade
Obesidade/metabolismo
Obesidade/fisiopatologia
Receptor de Endotelina A/metabolismo
Fluxo Sanguíneo Regional/fisiologia
Estatística como Assunto
Vasoconstrição/efeitos dos fármacos
Vasoconstrição/fisiologia
Vasoconstritores/farmacologia
Vasodilatação/efeitos dos fármacos
Vasodilatação/fisiologia
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Endothelin-1); 0 (Insulin); 0 (Peptide Fragments); 0 (Receptor, Endothelin A); 0 (Vasoconstrictor Agents); 0 (Vasodilator Agents); 9041-90-1 (Angiotensin I); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.10280


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[PMID]:28893641
[Au] Autor:de Oliveira Sá G; Dos Santos Neves V; de Oliveira Fraga SR; Souza-Mello V; Barbosa-da-Silva S
[Ad] Endereço:Institute of Biology, State University of Rio de Janeiro, RJ, Brazil.
[Ti] Título:High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high-fructose diets.
[So] Source:Life Sci;189:8-17, 2017 Nov 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed. MAIN METHODS: Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12-week HIIT protocol (T=trained group), while the other subgroup remained non-exercised (NT=not-trained group). KEY FINDINGS: HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high-fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF-T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT. SIGNIFICANCE: This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT.
[Mh] Termos MeSH primário: Treinamento Intervalado de Alta Intensidade
Hipertrofia Ventricular Esquerda/terapia
Resistência à Insulina/fisiologia
Sistema Renina-Angiotensina/fisiologia
Remodelação Ventricular/fisiologia
[Mh] Termos MeSH secundário: Angiotensina I/metabolismo
Animais
Pressão Sanguínea/fisiologia
Dieta Hiperlipídica
Frutose
Regulação da Expressão Gênica/fisiologia
Hipertensão/terapia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Fragmentos de Peptídeos/metabolismo
Peptidil Dipeptidase A/metabolismo
Distribuição Aleatória
Receptor Tipo 2 de Angiotensina/metabolismo
Renina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptide Fragments); 0 (Receptor, Angiotensin, Type 2); 30237-26-4 (Fructose); 9041-90-1 (Angiotensin I); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2); EC 3.4.23.15 (Renin); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE


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[PMID]:28874464
[Au] Autor:Cerniello FM; Carretero OA; Longo Carbajosa NA; Cerrato BD; Santos RA; Grecco HE; Gironacci MM
[Ad] Endereço:From the Departamento de Química Biológica, IQUIFIB-CONICET, Universidad de Buenos Aires, Argentina (F.M.C., N.L.C., B.D.C., M.M.G.); Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI (O.A.C.); Department of Physiology, Federal University of Minas Gerais, Belo Horizont
[Ti] Título:MAS1 Receptor Trafficking Involves ERK1/2 Activation Through a ß-Arrestin2-Dependent Pathway.
[So] Source:Hypertension;70(5):982-989, 2017 Nov.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The MAS1 receptor (R) exerts protective effects in the brain, heart, vessels, and kidney. R trafficking plays a critical function in signal termination and propagation and in R resensitization. We examined MAS1R internalization and trafficking on agonist stimulation and the role of ß-arrestin2 in the activation of ERK1/2 (extracellular signal-regulated kinase 1/2) and Akt after MAS1R stimulation. Human embryonic kidney 293T cells were transfected with the coding sequence for MAS1R-YFP (MAS1R fused to yellow fluorescent protein). MAS1R internalization was evaluated by measuring the MAS1R present in the plasma membrane after agonist stimulation using a ligand-binding assay. MAS1R trafficking was evaluated by its colocalization with trafficking markers. MAS1R internalization was blocked in the presence of shRNAcaveolin-1 and with dominant negatives for Eps15 (a protein involved in endocytosed Rs by clathrin-coated pits) and for dynamin. After stimulation, MAS1R colocalized with Rab11-a slow recycling vesicle marker-and not with Rab4-a fast recycling vesicle marker-or LysoTracker-a lysosome marker. Cells transfected with MAS1R showed an increase in Akt and ERK1/2 activation on angiotensin-(1-7) stimulation, which was blocked when the clathrin-coated pits pathway was blocked. Suppression of ß-arrestin2 by shRNA reduced the angiotensin-(1-7)-induced ERK1/2 activation, whereas Akt activation was not modified. We conclude that on agonist stimulation, MAS1R is internalized through clathrin-coated pits and caveolae in a dynamin-dependent manner and is then slowly recycled back to the plasma membrane. MAS1R induced Akt and ERK1/2 activation from early endosomes, and the activation of ERK1/2 was mediated by ß-arrestin2. Thus, MAS1R activity and density may be tightly controlled by the cell.
[Mh] Termos MeSH primário: Angiotensina I/metabolismo
Endocitose/fisiologia
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Fragmentos de Peptídeos/metabolismo
Transporte Proteico/fisiologia
Proteínas Proto-Oncogênicas/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
beta-Arrestina 2/metabolismo
[Mh] Termos MeSH secundário: Endossomos/fisiologia
Células HEK293
Seres Humanos
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptide Fragments); 0 (Proto-Oncogene Proteins); 0 (Receptors, G-Protein-Coupled); 0 (beta-Arrestin 2); 0 (proto-oncogene proteins c-mas-1); 9041-90-1 (Angiotensin I); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.09789


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[PMID]:28789938
[Au] Autor:Sukumaran V; Tsuchimochi H; Tatsumi E; Shirai M; Pearson JT
[Ad] Endereço:Department of Artificial Organs, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan; Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan. Electronic address: svkumar1979@ncvc.go.jp.
[Ti] Título:Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ACE-2/ANG 1-7/Mas receptor cascade.
[So] Source:Biochem Pharmacol;144:90-99, 2017 Nov 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hyperglycemia up-regulates intracellular angiotensin II (ANG-II) production in cardiac myocytes. This study investigated the hemodynamic and metabolic effects of azilsartan (AZL) treatment in a mouse model of diabetic cardiomyopathy and whether the cardioprotective effects of AZL are mediated by the angiotensin converting enzyme (ACE)-2/ANG 1-7/Mas receptor (R) cascade. Control db/+ and db/db mice (n=5 per group) were treated with vehicle or AZL (1 or 3mg/kg/d oral gavage) from the age of 8 to 16weeks. Echocardiography was then performed and myocardial protein levels of ACE-2, Mas R, AT R, AT R, osteopontin, connective tissue growth factor (CTGF), atrial natriuretic peptide (ANP) and nitrotyrosine were measured by Western blotting. Oxidative DNA damage and inflammatory markers were assessed by immunofluorescence of 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). Compared with db/+ mice, the vehicle-treated db/db mice developed obesity, hyperglycemia, hyperinsulinemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis. AZL treatment lowered blood pressure, fasting blood glucose and reduced peak plasma glucose during an oral glucose tolerance test. AZL-3 treatment resulted in a significant decrease in the expression of cytokines, oxidative DNA damage and cardiac dysfunction. Moreover, AZL-3 treatment significantly abrogated the downregulation of ACE-2 and Mas R protein levels in db/db mice. Furthermore, AZL treatment significantly reduced cardiac fibrosis, hypertrophy and their marker molecules (osteopontin, CTGF, TGF-ß1 and ANP). Short-term treatment with AZL-3 reversed abnormal cardiac structural remodeling and partially improved glucose metabolism in db/db mice by modulating the ACE-2/ANG 1-7/Mas R pathway.
[Mh] Termos MeSH primário: Angiotensina I/metabolismo
Benzimidazóis/uso terapêutico
Cardiomiopatias Diabéticas/tratamento farmacológico
Cardiomiopatias Diabéticas/metabolismo
Oxidiazóis/uso terapêutico
Fragmentos de Peptídeos/metabolismo
Peptidil Dipeptidase A/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Angiotensina I/antagonistas & inibidores
Animais
Benzimidazóis/farmacologia
Pressão Sanguínea/efeitos dos fármacos
Pressão Sanguínea/fisiologia
Cardiomiopatias Diabéticas/genética
Masculino
Camundongos
Camundongos Transgênicos
Oxidiazóis/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Estresse Oxidativo/fisiologia
Fragmentos de Peptídeos/antagonistas & inibidores
Proteínas Proto-Oncogênicas/antagonistas & inibidores
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Oxadiazoles); 0 (Peptide Fragments); 0 (Proto-Oncogene Proteins); 0 (Receptors, G-Protein-Coupled); 0 (proto-oncogene proteins c-mas-1); 9041-90-1 (Angiotensin I); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2); F9NUX55P23 (azilsartan); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE


  9 / 3693 MEDLINE  
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[PMID]:28674038
[Au] Autor:De Silva TM; Hu C; Kinzenbaw DA; Modrick ML; Sigmund CD; Faraci FM
[Ad] Endereço:From the Departments of Internal Medicine (T.M.D.S., D.A.K., M.L.M., F.M.F.) and Pharmacology (C.H., C.D.S., F.M.F.), Center for Hypertension Research, Carver College of Medicine, The University of Iowa; and Iowa City Veterans Affairs Healthcare System (F.M.F.).
[Ti] Título:Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator-Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7.
[So] Source:Hypertension;70(3):559-565, 2017 Sep.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pharmacological activation of PPAR-γ (peroxisome proliferator-activated receptor-γ) protects the vasculature. Much less is known on the cell-specific impact of PPAR-γ when driven by endogenous ligands. Recently, we found that endothelial PPAR-γ protects against angiotensin II-induced endothelial dysfunction. Here, we explored that concept further examining whether effects were sex dependent along with underlying mechanisms. We studied mice expressing a human dominant-negative mutation in PPAR-γ driven by the endothelial-specific vascular cadherin promoter (E-V290M), using nontransgenic littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from nontransgenic and E-V290M mice. Incubation of isolated arteries with angiotensin II (1 nmol/L) overnight had no effect in nontransgenic, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice ( <0.05). Endothelial function in E-V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS-2870), Rho kinase (Y-27632), ROCK2 (SLX-2119), NF-κB (nuclear factor-kappa B essential modulator-binding domain peptide), or interleukin-6 (neutralizing antibody). In addition, we hypothesized that PPAR-γ may influence the angiotensin 1-7 arm of the renin-angiotensin system. In the basilar artery, dilation to angiotensin 1-7 was selectively reduced in E-V290M mice by >50% ( <0.05), an effect reversed by Y-27632. Thus, effects of angiotensin II are augmented by interference with endothelial PPAR-γ through sex-independent mechanisms, involving oxidant-inflammatory signaling and ROCK2 (Rho kinase). The study also provides the first evidence that endothelial PPAR-γ interacts with angiotensin 1-7 responses. These critical roles for endothelial PPAR-γ have implications for pathophysiology and therapeutic approaches for vascular disease.
[Mh] Termos MeSH primário: Angiotensina II
Angiotensina I
PPAR gama/metabolismo
Fragmentos de Peptídeos
Doenças Vasculares
Vasodilatação
[Mh] Termos MeSH secundário: Amidas
Angiotensina I/metabolismo
Angiotensina I/farmacologia
Angiotensina II/metabolismo
Angiotensina II/farmacologia
Animais
Animais Geneticamente Modificados
Artérias Carótidas/efeitos dos fármacos
Artérias Carótidas/metabolismo
Feminino
Interleucina-6/metabolismo
Masculino
Camundongos
NF-kappa B/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Estresse Oxidativo/fisiologia
Fragmentos de Peptídeos/metabolismo
Fragmentos de Peptídeos/farmacologia
Piridinas
Sistema Renina-Angiotensina/efeitos dos fármacos
Sistema Renina-Angiotensina/fisiologia
Doenças Vasculares/metabolismo
Doenças Vasculares/fisiopatologia
Vasoconstritores/farmacologia
Vasodilatação/efeitos dos fármacos
Vasodilatação/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Interleukin-6); 0 (NF-kappa B); 0 (PPAR gamma); 0 (Peptide Fragments); 0 (Pyridines); 0 (Vasoconstrictor Agents); 11128-99-7 (Angiotensin II); 138381-45-0 (Y 27632); 9041-90-1 (Angiotensin I); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.09358


  10 / 3693 MEDLINE  
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[PMID]:28591164
[Au] Autor:Uchiyama T; Okajima F; Mogi C; Tobo A; Tomono S; Sato K
[Ad] Endereço:Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
[Ti] Título:Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue.
[So] Source:PLoS One;12(6):e0178769, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Obesity is associated with an increased risk of diabetes mellitus, hypertension, and renal dysfunction. Angiotensin 1-7 and alamandine are heptameric renin angiotensin system peptide hormones. Further, alamandine levels increase with renal dysfunction. In the cardiovascular system, angiotensin 1-7 and alamandine produce similar improvements and counterbalance angiotensin II in regulating vascular function. We aimed to determine whether the effect of alamandine on leptin expression and secretion in adipocytes was similar to that of angiotensin 1-7. APPROACH AND RESULTS: We studied isolated peri-renal visceral adipose tissue and peri-renal isolated visceral adipocytes from male Wistar rats. Angiotensin II from 0.01 to 10nM had no effect on leptin expression. Angiotensin 1-7 (1 nM) increased leptin secretion and expression, whereas alamandine (1 nM) decreased leptin secretion and expression in adipose tissue and isolated adipocytes and reduced blood leptin levels in vivo. These effects were mediated by Gq, c-Src, p38 mitogen-activated protein, and IκB activation. Additionally, alamandine induced nitric oxide expression via inducible nitric oxidase synthase and plasminogen activator inhibitor 1 expression in adipose tissue and isolated adipocytes. CONCLUSIONS: Angiotensin 1-7 and alamandine produced opposing effects on leptin expression and secretion in adipose tissue. This result suggests that the action of Mas (angiotensin 1-7 receptor) and Mas-related G-protein coupled receptor D in adipocytes exhibited opposing actions similar to angiotensin II type 1 and type 2 receptors.
[Mh] Termos MeSH primário: Tecido Adiposo/metabolismo
Leptina/metabolismo
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Oligopeptídeos/farmacologia
Quinases da Família src/metabolismo
[Mh] Termos MeSH secundário: Células 3T3-L1
Adipócitos/efeitos dos fármacos
Adipócitos/metabolismo
Tecido Adiposo/efeitos dos fármacos
Angiotensina I/farmacologia
Animais
Separação Celular
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo
Leptina/sangue
Masculino
Camundongos
Modelos Biológicos
NF-kappa B/metabolismo
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo II/metabolismo
Fragmentos de Peptídeos/farmacologia
Inibidor 1 de Ativador de Plasminogênio/metabolismo
Ratos Wistar
Receptores Acoplados a Proteínas-G/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Leptin); 0 (Mas-related receptor MrgD, rat); 0 (NF-kappa B); 0 (Oligopeptides); 0 (Peptide Fragments); 0 (Plasminogen Activator Inhibitor 1); 0 (Receptors, G-Protein-Coupled); 0 (alamandine); 31C4KY9ESH (Nitric Oxide); 9041-90-1 (Angiotensin I); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 2.7.10.2 (CSK tyrosine-protein kinase); EC 2.7.10.2 (src-Family Kinases); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178769



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