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1.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R513-R521, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34346721

RESUMO

Experiments aimed to evaluate the tissue distribution of Mas-related G protein-coupled receptor D (MrgD) revealed the presence of immunoreactivity for the MrgD protein in the rostral insular cortex (rIC), an important area for autonomic and cardiovascular control. To investigate the relevance of this finding, we evaluated the cardiovascular effects produced by the endogenous ligand of MrgD, alamandine, in this brain region. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in urethane anesthetized rats. Unilateral microinjection of equimolar doses of alamandine (40 pmol/100 nL), angiotensin-(1-7), angiotensin II, angiotensin A, and Mas/MrgD antagonist d-Pro7-Ang-1-7 (50 pmol/100 nL), Mas antagonist A779 (100 pmol/100 nL), or vehicle (0.9% NaCl) were made in different rats (n = 4-6/group) into rIC. To verify the specificity of the region, a microinjection of alamandine was also performed into intermediate insular cortex (iIC). Microinjection of alamandine in rIC produced an increase in MAP (Δ = 15 ± 2 mmHg), HR (Δ = 36 ± 4 beats/min), and RSNA (Δ = 31 ± 4%), but was without effects at iIC. Strikingly, an equimolar dose of angiotensin-(1-7) at rIC did not produce any change in MAP, HR, and RSNA. Angiotensin II and angiotensin A produced only minor effects. Alamandine effects were not altered by A-779, a Mas antagonist, but were completely blocked by the Mas/MrgD antagonist d-Pro7-Ang-(1-7). Therefore, we have identified a brain region in which alamandine/MrgD receptor but not angiotensin-(1-7)/Mas could be involved in the modulation of cardiovascular-related neuronal activity. This observation also suggests that alamandine might possess unique effects unrelated to angiotensin-(1-7) in the brain.


Assuntos
Angiotensina I/farmacologia , Pressão Arterial/efeitos dos fármacos , Sistema Cardiovascular/inervação , Córtex Cerebral/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Rim/inervação , Proteínas do Tecido Nervoso/agonistas , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Córtex Cerebral/fisiologia , Ligantes , Masculino , Microinjeções , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas/agonistas , Proteínas Proto-Oncogênicas/metabolismo , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Sistema Nervoso Simpático/fisiologia
2.
J Pharmacol Exp Ther ; 377(1): 64-74, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33495248

RESUMO

The in vivo application and efficacy of many therapeutic peptides is limited because of their instability and proteolytic degradation. Novel strategies for developing therapeutic peptides with higher stability toward proteolytic degradation would be extremely valuable. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body essential for the regulation of blood pressure and fluid balance. The RAS is composed of two opposing classic and protective arms. The balance between these two arms is critical for the homeostasis of the body's physiologic function. Activation of the RAS results in the suppression of its protective arm, which has been reported in inflammatory and pathologic conditions such as arthritis, cardiovascular diseases, diabetes, and cancer. Clinical application of angiotensin-(1-7) [Ang-(1-7)], a RAS critical regulatory peptide, augments the protective arm and restores balance hampered by its enzymatic and chemical instability. Several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches have been made. This review article provides an overview of efforts targeting the RAS protective arm. It provides a critical analysis of Ang-(1-7) or its homologs' novel drug delivery systems using different administration routes, their pharmacological characterization, and therapeutic potential in various clinical settings. SIGNIFICANCE STATEMENT: Ang-(1-7) is a unique peptide component of the renin-angiotensin system with vast potential for clinical applications that modulate various inflammatory diseases. Novel Ang-(1-7) peptide drug delivery could compensate its lack of stability for effective clinical application.


Assuntos
Angiotensina I/farmacologia , Anti-Hipertensivos/farmacologia , Hipoglicemiantes/farmacologia , Fragmentos de Peptídeos/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/administração & dosagem , Angiotensina I/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico
3.
Sci Rep ; 11(1): 610, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436885

RESUMO

Sepsis can lead to shock, multiple organ failure, and even death. Platelets play an active role in the pathogenesis of sepsis-induced multiple organ failure. Angiotensin (Ang)-(1-7), a biologically active peptide, counteracts various effects of Ang II and attenuates inflammatory responses, reactive oxygen species production, and apoptosis. We evaluated the effects of Ang-(1-7) on organ injury and platelet dysfunction in rats with endotoxaemia. We treated male Wistar rats with saline or lipopolysaccharide (LPS, 10 mg, intravenously) then Ang-(1-7) (1 mg/kg, intravenous infusion for 3 h beginning 30 min after LPS administration). We analysed several haemodynamic, biochemical, and inflammatory parameters, as well as platelet counts and aggregation. Ang-(1-7) improved hypotension and organ dysfunction, and attenuated plasma interleukin-6, chemokines and nitric oxide production in rats after LPS administration. The LPS-induced reduction in platelet aggregation, but not the decreased platelet count, was restored after Ang-(1-7) treatment. The protein expression of iNOS and IκB, but not phosphorylated ERK1/2 and p38, was diminished in Ang-(1-7)-treated LPS rats. The histological changes in liver and lung were significantly attenuated in Ang-(1-7)-treated LPS rats. Our results suggest that Ang-(1-7) ameliorates endotoxaemic-induced organ injury and platelet dysfunction, likely through the inhibition of the inflammatory response and nitric oxide production.


Assuntos
Angiotensina I/farmacologia , Plaquetas/efeitos dos fármacos , Endotoxemia/complicações , Hipotensão/prevenção & controle , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Insuficiência de Múltiplos Órgãos/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Animais , Plaquetas/patologia , Endotoxemia/induzido quimicamente , Hipotensão/etiologia , Hipotensão/patologia , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Sepse/complicações , Vasodilatadores/farmacologia
4.
J Pharmacol Exp Ther ; 376(2): 213-221, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33154104

RESUMO

Mouse mast cell protease 4 (mMCP-4), the murine functional analog to the human chymase, is a serine protease synthesized and stored in mast cell secretory granules. Our previous studies reported physiologic and pathologic roles for mMCP-4 in the maturation and synthesis of the vasoactive peptide endothelin-1 (ET-1) from its precursor, big ET-1. The aim of this study was to investigate the impact of mast cell degranulation or stabilization on mMCP-4-dependent pressor responses after the administration of big ET-1 or angiotensin I (Ang I). In anesthetized mice, mast cell degranulation induced by compound 48/80 (C48/80) or stabilization by cromolyn enhanced or repressed, respectively, the dose-dependent vasopressor responses to big ET-1 in wild-type (WT) mice but not in mMCP-4 knockout mice in a chymase inhibitor (TY-51469)-sensitive fashion. In addition, mMCP-4-dependent hydrolysis of the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin was depleted or enhanced in peritoneal mast cells isolated from mice pretreated with C48/80 or cromolyn, respectively. Furthermore, C48/80 or cromolyn markedly increased or abolished, respectively, ET-1 (1-31) conversion from exogenous big ET-1 in WT mice peritoneal fluid-isolated mast cells, in vitro. Finally, the vasopressor responses to Ang I were unaffected by mast cell activation or stabilization, whereas those induced by the angiotensin-converting enzyme-resistant Ang I analog, [Pro11, D-Ala12] Ang I, were potentiated by C48/80. Altogether, the present study shows that mast cell activation enhances the mMCP-4-dependent vasoactive properties of big ET-1 but not Ang I in the mouse model. SIGNIFICANCE STATEMENT: The current work demonstrates a significant role for mast cell stability in the cardiovascular pharmacology of big endothelin-1 but not angiotensin I in the murine systemic circulation.


Assuntos
Angiotensina I/farmacologia , Pressão Sanguínea , Degranulação Celular , Endotelina-1/farmacologia , Mastócitos/fisiologia , Serina Endopeptidases/metabolismo , Animais , Células Cultivadas , Quimases/antagonistas & inibidores , Cromolina Sódica/farmacologia , Inibidores Enzimáticos/farmacologia , Masculino , Estabilizadores de Mastócitos/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/citologia , Serina Endopeptidases/genética , Sulfonamidas/farmacologia , Tiofenos/farmacologia
5.
Am J Physiol Endocrinol Metab ; 320(1): E55-E70, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33103451

RESUMO

Osteoporosis, diabetes, and hypertension are common concurrent chronic disorders. This study aimed to explore the respective effects of angiotensin II (ANG II) and angiotensin(1-7) [ANG(1-7)], active peptides in the renin-angiotensin system, on osteoblasts and osteoclasts under high-glucose level, as well as to investigate the osteo-preservative effects of ANG II type 1 receptor (AT1R) blocker and ANG(1-7) in diabetic spontaneously hypertensive rats (SHR). ANG II and ANG(1-7), respectively, decreased and increased the formation of calcified nodules and alkaline phosphatase activity in MC3T3-E1 cells under high-glucose level, and respectively stimulated and inhibited the number of matured osteoclasts and pit resorptive area in RANKL-induced bone marrow macrophages. Olmesartan and Mas receptor antagonist A779 could abolish those effects. ANG II and ANG(1-7), respectively, downregulated and upregulated the expressions of osteogenesis factors in MC3T3-E1 cells. ANG II promoted the expressions of cathepsin K and MMP9 in RAW 264.7 cells, whereas ANG(1-7) repressed these osteoclastogenesis factors. ANG II rapidly increased the phosphorylation of Akt and p38 in RAW 264.7 cells, whereas ANG(1-7) markedly reduced the phosphorylation of p38 and ERK under high-glucose condition. After treatments of diabetic SHR with valsartan and ANG(1-7), a significant increase in trabecular bone area, bone mineral density, and mechanical strength was only found in the ANG(1-7)-treated group. Treatment with ANG(1-7) significantly suppressed the increase in renin expression and ANG II content in the bone of SHR. Taken together, ANG II/AT1R and ANG(1-7)/Mas distinctly regulated the differentiation and functions of osteoblasts and osteoclasts upon exposure to high-glucose condition. ANG(1-7) could protect SHR from diabetes-induced osteoporosis.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Conservadores da Densidade Óssea/farmacologia , Osso e Ossos/efeitos dos fármacos , Glucose/efeitos adversos , Fragmentos de Peptídeos/farmacologia , Células 3T3 , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Masculino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/prevenção & controle , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Ratos , Ratos Endogâmicos SHR
6.
Eur Respir J ; 57(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32764118

RESUMO

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.


Assuntos
Lesão Pulmonar Aguda/genética , Angiotensina I/metabolismo , COVID-19/epidemiologia , Permeabilidade Capilar/genética , Endotélio Vascular/metabolismo , Estrogênios/metabolismo , Pulmão/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/genética , Síndrome do Desconforto Respiratório/epidemiologia , Lesão Pulmonar Aguda/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensina I/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Permeabilidade Capilar/efeitos dos fármacos , Criança , Impedância Elétrica , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Técnicas In Vitro , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Ovariectomia , Fragmentos de Peptídeos/farmacologia , Fator de Ativação de Plaquetas/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , SARS-CoV-2 , Distribuição por Sexo , Fatores Sexuais , Regulação para Cima , Adulto Jovem
7.
J Cell Physiol ; 236(4): 3059-3072, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32964425

RESUMO

Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin-(1-7) is able to block T3-induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin-(1-7) effects. Angiotensin-(1-7) treatment increased nuclear FOXO3 levels and reduced p-FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin-(1-7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor-κB (NF-κB) were observed after angiotensin-(1-7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin-(1-7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF-κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin-(1-7), which may contribute to future therapeutic targets.


Assuntos
Angiotensina I/farmacologia , Catalase/metabolismo , Proteína Forkhead Box O3/metabolismo , Miócitos Cardíacos/patologia , NF-kappa B/metabolismo , Fragmentos de Peptídeos/farmacologia , Superóxido Dismutase-1/metabolismo , Tri-Iodotironina/efeitos adversos , Regulação para Cima , Animais , Antioxidantes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hipertrofia , Masculino , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Horm Behav ; 127: 104880, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129833

RESUMO

Alamandine (Ala1-Arg2-Val3-Tyr4-Ile5-His6-Pro7), a heptapeptide hormone of the renin-angiotensin system (RAS), exerts its effects through the Mas-related G-protein coupled receptor of the type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we tested the hypothesis that alamandine could attenuate the depression-like behavior observed in transgenic rats with low brain angiotensinogen, TGR (ASrAOGEN)680. Transgenic rats exhibited a significant increase in the immobility time in forced swim test, a phenotype reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas/MrgD receptor antagonist, prevented the antidepressant-like effect induced by this peptide demonstrating, for the first time, that alamandine through MrgD receptor, can modulate depression-like behavior in TGR (ASrAOGEN)680. This result shows an action of alamandine which strengthens the importance of the counter-regulatory arms of the RAS in fight and treatment of neuropsychiatric diseases.


Assuntos
Angiotensinogênio/genética , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Oligopeptídeos/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Angiotensina I/farmacologia , Angiotensinogênio/metabolismo , Animais , Encéfalo/metabolismo , Injeções Intraventriculares , Masculino , Proteínas do Tecido Nervoso/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo
9.
J Cell Physiol ; 236(1): 366-378, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32519379

RESUMO

The effects of the renin-angiotensin system (RAS) on stem cells isolated from human dental apical papilla (SCAPs) are completely unknown. Therefore, the aim of this study was to identify RAS components expressed in SCAPs and the effects of angiotensin (Ang) II and Ang-(1-7) on cell proliferation. SCAPs were collected from third molar teeth of adolescents and maintained in cell culture. Messenger RNA expression and protein levels of angiotensin-converting enzyme (ACE), ACE2, and Mas, Ang II type I (AT1) and type II (AT2) receptors were detected in SCAPs. Treatment with either Ang II or Ang-(1-7) increased the proliferation of SCAPs. These effects were inhibited by PD123319, an AT2 antagonist. While Ang II augmented mTOR phosphorylation, Ang-(1-7) induced ERK1/2 phosphorylation. In conclusion, SCAPs produce the main RAS components and both Ang II and Ang-(1-7) treatments induced cell proliferation mediated by AT2 activation through different intracellular mechanisms.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Proliferação de Células/efeitos dos fármacos , Papila Dentária/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Células-Tronco/efeitos dos fármacos , Adolescente , Células Cultivadas , Papila Dentária/metabolismo , Feminino , Humanos , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Peptidil Dipeptidase A/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Células-Tronco/metabolismo
10.
Viruses ; 12(12)2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33265982

RESUMO

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1-7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.


Assuntos
COVID-19/patologia , Modelos Teóricos , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/administração & dosagem , Angiotensina I/farmacologia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacologia , Enzima de Conversão de Angiotensina 2/administração & dosagem , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacologia , COVID-19/tratamento farmacológico , COVID-19/virologia , Simulação por Computador , Humanos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2 , Carga Viral
11.
Int J Mol Sci ; 21(24)2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33302427

RESUMO

Skeletal muscle atrophy, which occurs in lipopolysaccharide (LPS)-induced sepsis, causes a severe muscle function reduction. The increased autophagy contributes to sepsis-induced skeletal muscle atrophy in a model of LPS injection, increasing LC3II/LC3I ratio, autophagy flux, and autophagosomes. Angiotensin-(1-7) (Ang-(1-7)) has anti-atrophic effects via the Mas receptor in skeletal muscle. However, the impact of Ang-(1-7) on LPS-induced autophagy is unknown. In this study, we determined the effect of Ang-(1-7) on sepsis-induced muscle autophagy. C57BL6 wild-type (WT) mice and mice lacking the Mas receptor (KO Mas) were injected with LPS together with the systemic administration of Ang-(1-7) to determine autophagy in skeletal muscle. We also evaluated autophagy and p38 and c-Jun N-terminal kinase (JNK)activation. Our results show that Ang-(1-7) prevents LPS-induced autophagy in the diaphragm, tibialis anterior, and gastrocnemius of WT mice, which is demonstrated by a decrease in the LC3II/LC3I ratio and mRNA levels of lc3b and ctsl. This effect was lost in KO Mas mice, suggesting the role of the Mas receptor. The results in C2C12 cells show that Ang-(1-7) reduces several LPS-dependent effects, such as autophagy (LC3II/LC3I ratio, autophagic flux, and autophagosomes), activation of p38 and JNK, B-cell lymphoma-2 (BCL2) phosphorylation, and disassembly of the Beclin1/BCL2 complex. In conclusion, Ang-(1-7)/Mas receptor reduces LPS-induced autophagy in skeletal muscle. In vitro assays indicate that Ang-(1-7) prevents LPS-induced autophagy and modifies the MAPK signaling and the disassembly of a complex involved at the beginning of autophagy.


Assuntos
Angiotensina I/farmacologia , Autofagia , Músculo Esquelético/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Catepsina L/metabolismo , Linhagem Celular , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Peptides ; 134: 170409, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32950566

RESUMO

Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1-7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1-7), l-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1-7) effect was increased by l-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1-7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1-7) contributes to renovascular hypertension.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Hipertensão Renovascular/tratamento farmacológico , Bulbo/metabolismo , Fragmentos de Peptídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Modelos Animais de Doenças , Frequência Cardíaca , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/patologia , Masculino , Bulbo/efeitos dos fármacos , Ratos , Vasoconstritores/farmacologia
13.
J Pharmacol Exp Ther ; 375(2): 268-275, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32883832

RESUMO

Renin-angiotensin system (RAS) is involved in TGF-ß-mediated epithelial-to-mesenchymal transition (EMT) and is responsible for airway remodeling in refractory asthma. Obstructive sleep apnea (OSA), which affects RAS activity, is a risk factor for refractory asthma. We aimed to investigate how chronic intermittent hypoxia (IH), the main pathophysiology of OSA, exacerbates asthma and whether Ang-(1-7) protects against chronic IH-induced airway remodeling in asthma. We exposed ovalbumin (OVA)-challenged asthma mice to chronic IH and observed that chronic IH aggravated airway inflammation and collagen deposit in OVA-challenged mice. Compared with the OVA group, the OVA + chronic IH group had a lower expression level of epithelial marker E-cadherin and higher expression levels of mesenchymal markers α-smooth muscle actin and collagen IV in airway epithelia, accompanied with activation of TGF-ß/Smad pathway. These changes were reversed by the administration of Ang-(1-7). Consistently, Ang-(1-7) mitigated chronic IH-induced activation of TGF-ß-mediated EMT in lipopolysaccharide-treated bronchial epithelial cells in a dose-dependent manner, which was blocked by Ang-(1-7)-specific Mas receptor antagonist A779. Taken together, Ang-(1-7) rescued chronic IH-aggravated TGF-ß-mediated EMT to suppress airway remodeling, implying that RAS activity is involved in the mechanisms of OSA-related airway dysfunction in asthma. SIGNIFICANCE STATEMENT: OSA is a risk factor for refractory asthma. In this study, we aimed to explore the mechanisms of how OSA exacerbates refractory asthma. We found that chronic IH induces TGF-ß-mediated EMT and aggravates airway collagen deposit. We also found that Ang-(1-7) erased the aggravation of TGF-ß-mediated EMT and epithelial fibrosis upon chronic IH exposure. These findings provided new insights that the ACE2/Ang-(1-7)/Mas axis might be considered as a potential therapeutic target for patients with asthma and OSA.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Angiotensina I/farmacologia , Asma/tratamento farmacológico , Asma/patologia , Hipóxia/complicações , Fragmentos de Peptídeos/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Asma/complicações , Asma/metabolismo , Brônquios/patologia , Linhagem Celular , Doença Crônica , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Int J Mol Sci ; 21(17)2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32872192

RESUMO

The local renin-angiotensin system (RAS) plays an important role in the pathophysiology of the prostate, including cancer development and progression. The Ang-(1-9) and Ang-(3-7) are the less known active peptides of RAS. This study examines the influence of these two peptide hormones on the metabolic activity, proliferation and migration of prostate cancer cells. Significant changes in MTT dye reduction were observed depending on the type of angiotensin and its concentration as well as time of incubation. Ang-(1-9) did not regulate the 2D cell division of either prostate cancer lines however, it reduced the size of LNCaP colonies formed in soft agar, maybe through down-regulation of the HIF1a gene. Ang-(3-7) increased the number of PC3 cells in the S phase and improved anchorage-independent growth as well as mobility. In this case, a significant increase in MKI67, BIRC5, and CDH-1 gene expression was also observed as well as all members of the NF-kB family. Furthermore, we speculate that this peptide can repress the proliferation of LNCaP cells by NOS3-mediated G2/M cell cycle arrest. No changes in expression of BIRC5 and BCL2/BAX ratio were observed but a decrease mRNA proapoptotic BAD gene was seen. In the both lines, Ang-(3-7) improved ROCK1 gene expression however, increased VEGF and NOS3 mRNA was only seen in the PC3 or LNCaP cells, respectively. Interestingly, it appears that Ang-(1-9) and Ang-(3-7) can modulate the level of steroidogenic enzymes responsible for converting cholesterol to testosterone in both prostate cancer lines. Furthermore, in PC3 cells, Ang-(1-9) upregulated AR expression while Ang-(3-7) upregulated the expression of both estrogen receptor genes. Ang-(1-9) and Ang-(3-7) can impact on biological properties of prostate cancer cells by modulating inflammatory and steroidogenesis pathway genes, among others.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Fragmentos de Peptídeos/farmacologia , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Colesterol/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testosterona/metabolismo
15.
Biochem Pharmacol ; 180: 114190, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32768401

RESUMO

The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1-9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1-9), with special focus on the control of vascular smooth muscle cell phenotype. Angiotensin-(1-9) decreased blood pressure and aorta media thickness in spontaneously hypertensive rats. Reduction of media thickness was associated with decreased vascular smooth muscle cell proliferation. In the A7r5 VSMC cell line and in primary cultures of rat aorta smooth muscle cells, angiotensin-(1-9) did not modify basal proliferation. However, angiotensin-(1-9) inhibited proliferation, migration and contractile protein decrease induced by platelet derived growth factor-BB. Moreover, angiotensin-(1-9) reduced Akt and FoxO1 phosphorylation at 30 min, followed by an increase of total FoxO1 protein content. Angiotensin-(1-9) effects were blocked by the AT2R antagonist PD123319, Akt-Myr overexpression and FoxO1 siRNA. These data suggest that angiotensin-(1-9) inhibits vascular smooth muscle cell dedifferentiation by an AT2R/Akt/FoxO1-dependent mechanism.


Assuntos
Angiotensina I/farmacologia , Anti-Hipertensivos/farmacologia , Desdiferenciação Celular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Angiotensina I/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Desdiferenciação Celular/fisiologia , Linhagem Celular , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Remodelação Vascular/fisiologia
16.
Biochim Biophys Acta Mol Cell Res ; 1867(11): 118804, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32738252

RESUMO

The movement of cell-bound membrane vesicles (CBMVs) on migrating cells is poorly understood. We hypothesized that the movement of CBMVs on migrating cells is different from that on non-migrating cells and can be interfered by external stimuli. To test it, single-vesicle tracking was performed to analyze motion type, speed, displacement, and direction of CBMVs on migrating cells treated with different reagents (Ang-1, TNF-α, LPS, VEGFα, endostatin, Cytochalasin D, and nocodazole) among which the former four promoted cell migration whereas the others inhibited cell migration. We found that cell migration changed CBMVs from non-directed to directed motion and that most CBMVs on untreated migrating cells moved along the migration axis. Interestingly, the migration-promoting reagents played positive roles in CBMV movement (improving directed motion, speed and/or maximal displacement, upregulating the amount of vesicles moving in migration direction) whereas the migration-inhibiting reagents played negative roles (impairing/abolishing directed motion, speed and/or maximal displacement, downregulating the vesicles moving forward or causing an even distribution of motion direction). The cytoskeleton (particularly microtubules) probably played vital roles in CBMV movement on migrating cells and mediated the effects of stimuli on vesicle movement. The data may provide important information for understanding the properties, behaviors, and functions of CBMVs.


Assuntos
Membrana Celular/genética , Movimento Celular/genética , Citoesqueleto/efeitos dos fármacos , Microtúbulos/genética , Angiotensina I/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Citocalasina D/farmacologia , Citoesqueleto/genética , Endostatinas/farmacologia , Humanos , Microtúbulos/efeitos dos fármacos , Nocodazol/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética
17.
Oxid Med Cell Longev ; 2020: 2862631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802261

RESUMO

As progressive organ shortage in cardiac transplantation demands extension of donor criteria, effort is needed to optimize graft survival. Reactive oxygen and nitrogen species, generated during organ procurement, transplantation, and reperfusion, contribute to acute and late graft dysfunction. The combined application of diverse substances acting via different molecular pathways appears to be a reasonable approach to face the complex mechanism of ischemia reperfusion injury. Thus, an antioxidant solution containing α-ketoglutaric acid, 5-hydroxymethylfurfural, N-acetyl-L-methionine, and N-acetyl-selenium-L-methionine was combined with endogenous angiotensin-(1-7). Its capacity of myocardial protection was investigated in isolated Langendorff-perfused rat hearts subjected to warm and cold ischemia. The physiological cardiac parameters were assessed throughout the experiments. Effects were evaluated via determination of the oxidative stress parameters malondialdehyde and carbonyl proteins as well as immunohistochemical and ultrastructural tissue analyses. It was shown that a combination of 20% (v/v) antioxidant solution and 220 pM angiotensin-(1-7) led to the best results with a preservation of heart tissue against oxidative stress and morphological alteration. Additionally, immediate cardiac recovery (after warm ischemia) and normal physiological performance (after cold ischemia) were recorded. Overall, the results of this study indicate substantial cardioprotection of the novel combination with promising prospective for future clinical use.


Assuntos
Angiotensina I/uso terapêutico , Antioxidantes/uso terapêutico , Coração/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos
18.
Clin Sci (Lond) ; 134(17): 2263-2277, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32803259

RESUMO

Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy and is often refractory to pharmacological treatment. In this scenario, extensive research has identified components of the renin-angiotensin system (RAS) as potential therapeutic targets. Therefore, the aim of the present study was to evaluate the effects of long-term treatment with angiotensin-(1-7) [Ang-(1-7)] in male Wistar rats with TLE induced by pilocarpine (PILO). Rats with TLE were submitted to intracerebroventricular (icv) infusion of Ang-(1-7) (200 ng/kg/h) for 28 days, starting at the first spontaneous motor seizure (SMS). Body weight, food intake, and SMS were evaluated daily. Behavioral tests and hippocampal protein levels were also evaluated at the end of the treatment. Ang-(1-7) treatment reduced the frequency of SMS and attenuated low anxiety levels, increased locomotion/exploration, and reduced body weight gain that was induced by TLE. Moreover, Ang-(1-7) positively regulated the hippocampal levels of antioxidant protein catalase and antiapoptotic protein B-cell lymphoma 2 (Bcl-2), as well as mammalian target of rapamycin (mTOR) phosphorylation, which were reduced by TLE. The hippocampal up-regulation of angiotensin type 1 receptor induced by TLE was also attenuated by Ang-(1-7), while the Mas receptor (MasR) was down-regulated compared with epilepsy. These data show that Ang-(1-7) presents an antiepileptic effect, increasing neuroprotection markers and reducing SMS frequency, body weight, and behavior impairments found in TLE. Therefore, Ang-(1-7) is a promising coadjutant therapeutic option for the treatment of TLE.


Assuntos
Angiotensina I/uso terapêutico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Anticonvulsivantes/farmacologia , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Teste de Labirinto em Cruz Elevado , Epilepsia do Lobo Temporal/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Infusões Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fotoperíodo , Ratos Wistar , Ganho de Peso/efeitos dos fármacos
19.
Pancreas ; 49(7): 960-966, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32658081

RESUMO

OBJECTIVES: The aim of this study was to investigate the changes of pancreatic microvascular vasomotion and blood distribution pattern in acute pancreatitis (AP), and whether Angiotensin (Ang)-(1-7) treatment could restore pancreatic microcirculation profiles. METHODS: Mice were randomly separated into control, AP, and Ang-(1-7)-treated AP (A-AP) group. Acute pancreatitis was induced in mice by intraperitoneal injection of cerulein and lipopolysaccharide. Pancreatitis was confirmed by histopathology, serum amylase, and high-sensitive C-reactive protein. Pancreatic microvascular vasomotion and blood distribution pattern in AP progression were assessed by laser Doppler. Meanwhile, ultrastructural changes of pancreatic microcirculation, including microvascular cavity and wall and endothelial mitochondria, were evaluated by transmission electron microscopy. RESULTS: Acute pancreatitis mice exhibited pathological pancreatic injuries with lower blood distribution pattern and decreased average blood perfusion, relative velocity, effective frequency, and amplitude of microvascular vasomotion. The pancreatic pathological injuries in Ang-(1-7)-treated mice were significantly alleviated. Consistently, Ang-(1-7) treatment led to a restoration in pancreatic microcirculation profiles. Furthermore, non-Ang-(1-7)-treated mice showed an irregular microvascular wall, narrow cavity, and swelling mitochondria, and these ultrastructural impairments were reversed by Ang-(1-7) administration. CONCLUSIONS: Pancreatic microcirculation profiles are abnormal in the progression of AP. Angiotensin-(1-7) administration could restore functional status of pancreatic microcirculation.


Assuntos
Angiotensina I/farmacologia , Microcirculação/efeitos dos fármacos , Pâncreas/irrigação sanguínea , Pancreatite/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Animais , Ceruletídeo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/ultraestrutura , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Microcirculação/fisiologia , Microscopia Eletrônica de Transmissão , Pancreatite/induzido quimicamente , Pancreatite/fisiopatologia
20.
Int J Mol Sci ; 21(14)2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32698498

RESUMO

Angiotensin (Ang)-(1-7) is a beneficial renin-angiotensin system (RAS) hormone that elicits protective cardiometabolic effects in young animal models of hypertension, obesity, and metabolic syndrome. The impact of Ang-(1-7) on cardiovascular and metabolic outcomes during aging, however, remains unexplored. This study tested the hypothesis that Ang-(1-7) attenuates age-related elevations in blood pressure and insulin resistance in mice. Young adult (two-month-old) and aged (16-month-old) male C57BL/6J mice received Ang-(1-7) (400 ng/kg/min) or saline for six-weeks via a subcutaneous osmotic mini-pump. Arterial blood pressure and metabolic function indices (body composition, insulin sensitivity, and glucose tolerance) were measured at the end of treatment. Adipose and cardiac tissue masses and cardiac RAS, sympathetic and inflammatory marker gene expression were also measured. We found that chronic Ang-(1-7) treatment decreased systolic and mean blood pressure, with a similar trend for diastolic blood pressure. Ang-(1-7) also improved insulin sensitivity in aged mice to levels in young mice, without effects on glucose tolerance or body composition. The blood pressure-lowering effects of Ang-(1-7) in aged mice were associated with reduced sympathetic outflow to the heart. These findings suggest Ang-(1-7) may provide a novel pharmacological target to improve age-related cardiometabolic risk.


Assuntos
Angiotensina I/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Resistência à Insulina , Fragmentos de Peptídeos/farmacologia , Envelhecimento/efeitos dos fármacos , Angiotensina I/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Glucose/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/metabolismo , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/administração & dosagem , Sistema Renina-Angiotensina/efeitos dos fármacos
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