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1.
Biomed Environ Sci ; 32(6): 419-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262387

RESUMO

OBJECTIVE: Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang (1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. METHODS: HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin (α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang (1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. RESULTS: Ang (1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang (1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang (1-7) increased the levels of ACE2 and Ang (1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang (1-7) in fibroblasts stimulated by Ang II. CONCLUSION: Ang (1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang (1-7)-Mas axis.


Assuntos
Angiotensina II/sangue , Angiotensina I/uso terapêutico , Pulmão/metabolismo , Miofibroblastos/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Silicose/prevenção & controle , Actinas/metabolismo , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Silicose/metabolismo , Silicose/patologia
2.
Crit Care Clin ; 35(2): 213-227, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784605

RESUMO

Classic and nonclassic renin-angiotensin systems (RAS) are 2 sides of an ubiquitous endocrine/paracrine cascade regulating blood pressure and homeostasis. Angiotensin II and angiotensin-converting enzyme (ACE) levels are associated with severity of disease in the critically ill, and are central to the physiology and the pathogenesis of circulatory shock. Angiotensin (1-7) and ACE2 act as an endogenous counterregulatory arm to the angiotensin II/ACE axis. The tissue-based RAS has paracrine effects dissociated from those of the circulating RAS. Exogenous angiotensin II or ACE2 may improve the outcome of septic shock and acute respiratory distress syndrome, respectively.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Angiotensina II/uso terapêutico , Angiotensina I/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Sistema Renina-Angiotensina/fisiologia , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Vasoconstritores/uso terapêutico , Lesão Renal Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/fisiologia , Estado Terminal , Feminino , Homeostase/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Choque Séptico/fisiopatologia
3.
Peptides ; 112: 78-84, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30529303

RESUMO

Native angiotensin-(1-7) exerts many therapeutic effects. However, it is rapidly degraded by ACE and other peptidases. This drawback is largely eliminated for lanthionine-stabilized angiotensin-(1-7), termed cAng-(1-7), which is fully resistant to ACE and has strongly increased resistance to other peptidases. Goal of the present study was to test whether cAng-(1-7) has therapeutic activity in diabetes mouse models: in a multiple low dose streptozotocin-induced model of type I diabetes and / or in a db/db model of type II diabetes. In the type I diabetes model cAng-(1-7) caused in an increase in the insulin level of 133% in week 4 (p < 0.001) compared to vehicle, and in the type II diabetes model an increase of 55% of the insulin level in week 8 (p < 0.05) compared to vehicle. cAng-(1-7) reduced blood glucose levels in the type I model by 37% at day 22 (p < 0.001) and in the type II diabetes model by 17% at day 63 of treatment (p < 0.001) and in an oral glucose tolerance test in a type II diabetes model, by 17% at week 4 (p < 0.01). cAng-(1-7) also caused a reduction of glycated hemoglobin levels in the type II diabetes model of 21% in week 6 (p < 0,001). These data are consistent with therapeutic potential of cAng-(1-7) in type I and II diabetes.


Assuntos
Alanina/análogos & derivados , Angiotensina I/farmacologia , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/sangue , Fragmentos de Peptídeos/farmacologia , Sulfetos/química , Alanina/química , Angiotensina I/química , Angiotensina I/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Feminino , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Estreptozocina/toxicidade , Resultado do Tratamento
4.
Int J Sports Med ; 39(10): 743-748, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29940668

RESUMO

The development of new strategies to attenuate exercise-induced muscle damage may be helpful for training regimens. The aim of this study was to determine whether a oral formulation of angiotensin Ang-(1-7)[HPßCD/Ang-(1-7)] is effective to reduce pain, and muscle damage markers after eccentric-overload exercise. HPßCD (Placebo) and HPßCD/Ang-(1-7) (Ang-(1-7) group were treated for 7 days (one capsule/day). The pain was measured by visual analogue scale, maximal strength (MS) using force platform. Blood samples were collected for cytokines and creatine kinase (CK) analysis. The Ang-(1-7)-treated group reported less pain immediately (3.46±0.64 vs. placebo 3.80±0.77 cm) and 24 h after exercise (3.07±0.71 vs. 3.73±0.58 cm placebo) and higher MS at 24 h (24±12 N) and 48 h (30±15 N) vs. placebo (-8±9 N and -10±9 N). The CK for Ang-(1-7) (0.5±0.1 and 0.9±0.2 U/L) were lower at 48 and 72 h vs. placebo (fold changes of 1.7±0.5 and 1.5±0.3 U/L). The TNF-α level was lower in the treated group post-exercise (38±2.5 pg/ml) vs. placebo (45±2.9 pg/ml) but no significant changes were observed for IL-6 and IL-10. Our data indicate that treatment with Ang-(1-7) may attenuate pain, some of the muscle damage markers and improves performance following eccentric exercise.


Assuntos
Angiotensina I/uso terapêutico , Suplementos Nutricionais , Exercício/fisiologia , Músculo Esquelético/lesões , Mialgia/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina , Adulto , Biomarcadores/sangue , Creatina Quinase/sangue , Citocinas/sangue , Método Duplo-Cego , Excipientes , Teste de Esforço , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Força Muscular/fisiologia , RNA Mensageiro/metabolismo , Adulto Jovem
5.
Fundam Clin Pharmacol ; 32(1): 14-25, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28833476

RESUMO

Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hallmark of heart failure (HF). It can be induced by the abnormal elevation of several endogenous factors including angiotensin II (Ang II), which is generated from its precursor angiotensin I (Ang I) by the action of angiotensin-converting enzyme. The inhibition of this enzyme or the blockade of the Ang II receptors demonstrated a high clinical value against the progression of HF. Ang I and Ang II may also be converted into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9), respectively, by the action of angiotensin-converting enzyme 2. Both derivatives demonstrated a promising anticardiac remodeling activity especially against the detrimental effects of Ang II. This manuscript thoroughly reviews the available in vitro and in vivo data on Ang 1-7 and Ang 1-9 in the context of the treatment of HF and discusses the associated molecular mechanisms and the trials to clinically utilize Ang 1-7 mimetics for the treatment of that disease.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Peptidil Dipeptidase A/metabolismo , Angiotensina I/efeitos adversos , Angiotensina I/metabolismo , Animais , Fármacos Cardiovasculares/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Mimetismo Molecular , Terapia de Alvo Molecular , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
6.
J Renin Angiotensin Aldosterone Syst ; 18(3): 1470320317729281, 2017 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28877652

RESUMO

INTRODUCTION: The effect of Angiotensin-(1-7) (Ang-(1-7)) on atrial autonomic remodeling is still unknown. We hypothesized that Ang-(1-7) could inhibit sympathetic nerve remodeling in a canine model of chronic atrial tachycardia. MATERIALS AND METHODS: Eighteen dogs were randomly assigned to sham group, pacing group and Ang-(1-7) group. Rapid atrial pacing was maintained for 14 days in the pacing and Ang-(1-7) groups. Ang-(1-7) was administered intravenously in the Ang-(1-7) group. The atrial effective refractory period and atrial fibrillation inducibility level were measured at baseline and under sympathetic nerve stimulation after 14 days of measurement. The atrial sympathetic nerves labeled with tyrosine hydroxylase were detected using immunohistochemistry and Western blotting, and tyrosine hydroxylase and nerve growth factor mRNA levels were measured by reverse transcription polymerase chain reaction. RESULTS: Pacing shortened the atrial effective refractory period and increased the atrial fibrillation inducibility level at baseline and under sympathetic nerve stimulation. Ang-(1-7) treatment attenuated the shortening of the atrial effective refractory period and the increase in the atrial fibrillation inducibility level. Immunohistochemistry and Western blotting showed sympathetic nerve hyperinnervation in the pacing group, while Ang-(1-7) attenuated sympathetic nerve proliferation. Ang-(1-7) alleviated the pacing-induced increases in tyrosine hydroxylase and nerve growth factor mRNA expression levels. CONCLUSION: Ang-(1-7) can attenuate pacing-induced atrial sympathetic hyperinnervation.


Assuntos
Angiotensina I/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Sistema Nervoso Simpático/patologia , Sistema Nervoso Simpático/fisiopatologia , Taquicardia/tratamento farmacológico , Taquicardia/fisiopatologia , Angiotensina I/farmacologia , Animais , Fibrilação Atrial/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Período Refratário Eletrofisiológico/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia/enzimologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
7.
Dev Comp Immunol ; 74: 200-208, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28487234

RESUMO

We recently demonstrated Ang 1-7 reduced inflammation in the dextran sulfate sodium (DSS) colitis model. In this study we examined the effect of Ang 1-7 on modulation of plasma levels of selected cytokines and chemokines and immune cell effector functions (apoptosis, chemotaxis and superoxide release) in vitro. The degree of neutrophil recruitment to the colon was assessed by immunofluorescence and myeloperoxidase activity. Daily Ang 1-7 treatment at 0.01 mg/kg dose which previously ameliorated colitis severity, showed a significant reduction in circulating levels of several cytokines and chemokines, and neutrophil recruitment to the colonic tissue. It also significantly enhanced immune cell apoptosis, and reduced neutrophil chemotaxis and superoxide release in vitro. In contrast, daily administration of the Ang 1-7R antagonist A779 which previously worsened colitis severity showed significant up-regulation of specific mediators. Our results demonstrate a novel anti-inflammatory action of Ang 1-7 through modulation of plasma levels of cytokines/chemokines and immune cell activity.


Assuntos
Angiotensina I/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colite/terapia , Colo/imunologia , Neutrófilos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/antagonistas & inibidores , Angiotensina II/administração & dosagem , Angiotensina II/análogos & derivados , Animais , Apoptose , Movimento Celular , Quimiocinas/sangue , Quimiotaxia , Colite/imunologia , Citocinas/sangue , Sulfato de Dextrana/imunologia , Imunidade Celular , Imunomodulação , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/antagonistas & inibidores , Sistema Renina-Angiotensina , Superóxidos/metabolismo
8.
Int J Nanomedicine ; 12: 1985-1999, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28331320

RESUMO

Angiotensin (1-7) (Ang-(1-7)) is a bioactive heptapeptide with a short half-life and has beneficial effects in several tissues - among them, skeletal muscle - by preventing muscle atrophy. Dendrimers are promising vehicles for the protection and transport of numerous bioactive molecules. This work explored the use of a neutral, non-cytotoxic hydroxyl-terminated poly(amidoamine) (PAMAM-OH) dendrimer as an Ang-(1-7) carrier. Bioinformatics analysis showed that the Ang-(1-7)-binding capacity of the dendrimer presented a 2:1 molar ratio. Molecular dynamics simulation analysis revealed the capacity of neutral PAMAM-OH to protect Ang-(1-7) and form stable complexes. The peptide coverage ability of the dendrimer was between ~50% and 65%. Furthermore, an electrophoretic mobility shift assay demonstrated that neutral PAMAM-OH effectively bonded peptides. Experimental results showed that the Ang-(1-7)/PAMAM-OH complex, but not Ang-(1-7) alone, had an anti-atrophic effect when administered intraperitoneally, as evaluated by muscle strength, fiber diameter, myofibrillar protein levels, and atrogin-1 and MuRF-1 expressions. The results of the Ang-(1-7)/PAMAM-OH complex being intraperitoneally injected were similar to the results obtained when Ang-(1-7) was systemically administered through mini-osmotic pumps. Together, the results suggest that Ang-(1-7) can be protected for PAMAM-OH when this complex is intraperitoneally injected. Therefore, the Ang-(1-7)/PAMAM-OH complex is an efficient delivery method for Ang-(1-7), since it improves the anti-atrophic activity of this peptide in skeletal muscle.


Assuntos
Angiotensina I/uso terapêutico , Dendrímeros/química , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , Transtornos Musculares Atróficos/tratamento farmacológico , Transtornos Musculares Atróficos/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Ensaio de Desvio de Mobilidade Eletroforética , Imobilização , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Transtornos Musculares Atróficos/patologia , Cadeias Pesadas de Miosina/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeos/uso terapêutico , Proteínas Ligases SKP Culina F-Box/metabolismo , Eletricidade Estática , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
9.
Can J Cardiol ; 33(7): 943-946, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28279521

RESUMO

Heart failure (HF) is a common cause of death and disability and a major economic burden in industrialized nations. Heart disease remains the leading cause of death in North America, with ischemic and hypertensive heart disease as the leading cause of HF. Various basic and clinical studies have established the role of an activated renin-angiotensin (Ang) system and Ang II generation in the progression of HF. Inhibition of an activated renin-Ang system using Ang-converting enzyme inhibitors, Ang II type 1 receptor blockers, and mineralocorticoid receptors antagonists have shown clinical benefits in patients with HF, although, largely limited to HF with reduced ejection fraction (HF-rEF). In contrast, there is no approved pharmacotherapy for HF with preserved ejection fraction (HF-pEF). Ang-converting enzyme (ACE) 2 (ACE2) is a homolog of ACE, which, being a monocarboxypeptidase converts Ang II into Ang 1-7 and is downregulated in HF. Various preclinical studies have shown a potent cardioprotective role of ACE2/Ang 1-7 axis in HF, which counter-regulates the ACE/Ang II/Ang II type 1 receptor axis. Importantly, ACE2 and Ang 1-7 show substantial benefit in preclinical models of HF-pEF and HF-rEF. Improvement in endothelial dysfunction, suppression of tissue inflammation and myocardial fibrosis, correction of metabolic dysfunction, and reversal of pathological hypertrophy are the key beneficial effects seen when ACE2 or Ang 1-7 action are enhanced. Clinical benefit of recombinant human ACE2 and Ang 1-7 need to be evaluated in patients with HF-rEF and HF-pEF.


Assuntos
Angiotensina I/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Peptidil Dipeptidase A/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Sistema Renina-Angiotensina , Insuficiência Cardíaca/metabolismo , Humanos , Vasodilatadores/uso terapêutico
10.
Behav Neurosci ; 131(1): 99-114, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28054808

RESUMO

Patients with congestive heart failure (CHF) have increased hospital readmission rates and mortality if they are concomitantly diagnosed with cognitive decline and memory loss. Accordingly, we developed a preclinical model of CHF-induced cognitive impairment with the goal of developing novel protective therapies against CHF related cognitive decline. CHF was induced by ligation of the left coronary artery to instigate a myocardial infarction (MI). By 4- and 8-weeks post-MI, CHF mice had approximately a 50% and 70% decline in ejection fraction as measured by echocardiography. At both 4- and 8-weeks post-MI, spatial memory performance in CHF mice as tested using the Morris water task was significantly impaired as compared with sham. In addition, CHF mice had significantly worse performance on object recognition when compared with shams as measured by discrimination ratios during the novel object recognition NOR task. At 8-weeks post-MI, a subgroup of CHF mice were given Angiotensin (Ang)-(1-7) (50mcg/kg/hr) subcutaneously for 4 weeks. Following 3 weeks treatment with systemic Ang-(1-7), the CHF mice NOR discrimination ratios were similar to shams and significantly better than the performance of CHF mice treated with saline. Ang-(1-7) also improved spatial memory in CHF mice as compared with shams. Ang-(1-7) had no effect on cardiac function. Inflammatory biomarker studies from plasma revealed a pattern of neuroprotection that may underlie the observed improvements in cognition. These results demonstrate a preclinical mouse model of CHF that exhibits both spatial memory and object recognition dysfunction. Furthermore, this CHF-induced cognitive impairment is attenuated by treatment with systemic Ang-(1-7). (PsycINFO Database Record


Assuntos
Angiotensina I/administração & dosagem , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Insuficiência Cardíaca/complicações , Fragmentos de Peptídeos/administração & dosagem , Angiotensina I/uso terapêutico , Animais , Disfunção Cognitiva/etiologia , Insuficiência Cardíaca/fisiopatologia , Inflamação/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Fragmentos de Peptídeos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Acuidade Visual/efeitos dos fármacos
11.
Int J Cardiol ; 236: 405-412, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28096047

RESUMO

BACKGROUND: Angiotensin-(1-7) [Ang-(1-7)] exhibits cardiovascular effects opposite those of angiotensin II (Ang II), thus providing protection against heart disease. However, how Ang-(1-7) imparts cardioprotection is unclear, and its direct cardiac effects are controversial. Whether heart failure (HF) alters cardiac contractile responses to Ang-(1-7) remains undetermined. We tested the hypothesis that in HF, Ang-(1-7) may produce positive modulation on [Ca2+]i regulation, enhancing left ventricular (LV) and myocyte contraction and relaxation via Ang-(1-7) Mas receptor coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism. METHODS AND RESULTS: We measured LV contractility changes after Ang-(1-7) (650ng/kg, iv) and compared myocyte functional and [Ca2+]i transient ([Ca2+]iT) responses to Ang-(1-7) superfusion in 24 normal rats and 34 rats with isoproterenol-induced HF (3months after 170mg/kg, s.q. for 2days). To assess the mechanisms of altered HF responses to Ang-(1-7), subsets of HF myocytes were pretreated to inhibit NO synthase (L-NAME), BK (HOE-140), and Mas receptor (A-779) followed with Ang-(1-7). In normal rats, Ang-(1-7) produced no significant changes in LV and myocyte function. In HF rats, Ang-(1-7) significantly augmented LV contractility and relaxation with increased EES (51%), but decreased τ compared to baseline. Ang-(1-7) also significantly increased myocyte contraction (dL/dtmax, 30%), relaxation (dR/dtmax, 41%), and [Ca2+]iT. L-NAME increased, HOE-140 decreased, and A-779 prevented HF myocyte contractile responses to Ang-(1-7). CONCLUSIONS: In a rat model of HF, Ang-(1-7) increases [Ca2+]iT, and produces positive inotropic and lusitropic effects in the LV and myocytes. These effects are mediated by the Mas receptor and involve activation of NO/BK pathways.


Assuntos
Angiotensina I/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Angiotensina I/farmacologia , Animais , Masculino , Miócitos Cardíacos/fisiologia , Fragmentos de Peptídeos/farmacologia , Ratos , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Função Ventricular Esquerda/fisiologia
12.
Oncotarget ; 8(1): 354-363, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27861149

RESUMO

Ang-(1-7) inhibits lung cancer cell growth both in vitro and in vivo. However, the molecular mechanism of action is unclear and also the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Here, we have demonstrated that Ang- (1-7) inhibits lung cancer cell growth by interrupting pre-replicative complex assembly and restrains epithelial-mesenchymal transition via Cdc6 inhibition. Furthermore, we constructed a mutant adeno-associated viral vector AAV8 (Y733F) that produced stable and high efficient Ang-(1-7) expression in a xenograft tumor model. The results show that AAV8-mediated Ang-(1-7) over-expression can remarkably suppress tumor growth in vivo by down-regulating Cdc6 and anti-angiogenesis. Ang-(1-7) over-expression via the AAV8 method may be a promising strategy for lung cancer treatment.


Assuntos
Angiotensina I/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Dependovirus/genética , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Fragmentos de Peptídeos/metabolismo , Angiotensina I/genética , Angiotensina I/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Replicação do DNA , Regulação para Baixo , Transição Epitelial-Mesenquimal , Feminino , Vetores Genéticos/genética , Humanos , Imuno-Histoquímica , Pulmão/irrigação sanguínea , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Complexos Multienzimáticos/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/uso terapêutico , Proteólise , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Am Coll Cardiol ; 68(24): 2652-2666, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27978950

RESUMO

BACKGROUND: Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI). OBJECTIVES: The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. METHODS: C57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model. RESULTS: Gene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism. CONCLUSIONS: Our novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A-dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.


Assuntos
Angiotensina I/uso terapêutico , Infarto do Miocárdio/terapia , Fragmentos de Peptídeos/uso terapêutico , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular , Animais , Células Cultivadas , Modelos Animais de Doenças , Terapia Genética , Ventrículos do Coração/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Volume Sistólico , Sístole
14.
Cell Physiol Biochem ; 40(1-2): 27-38, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27842312

RESUMO

BACKGROUND: Transforming growth factor type beta 1 (TGF-ß1) produces skeletal muscle atrophy. Angiotensin-(1-7) (Ang-(1-7)), through the Mas receptor, prevents the skeletal muscle atrophy induced by sepsis, immobilization, or angiotensin II (Ang-II). However, the effect of Ang-(1-7) on muscle wasting induced by TGF-ß1 is unknown. AIM: To evaluate whether Ang-(1-7)/Mas receptor axis could prevent the skeletal muscle atrophy induced by TGF-ß1. METHODS: This study assessed the atrophic effect of TGF-ß1 in C2C12 myotubes and mice in absence or presence of Ang-(1-7), and the receptor participation using A779, an antagonist of the Mas receptor. The levels of myosin heavy chain (MHC), polyubiquitination, and MuRF-1 were detected by western blot. Myotube diameter was also evaluated. In vivo analysis included the muscle strength, fibre diameter, MHC and MuRF-1 levels by western blot, and ROS levels by DCF probe detection. RESULTS: The results showed that Ang-(1-7) prevented the increase in MuRF-1 and polyubiquitined protein levels, the decrease of MHC levels, the myotubes/fibre diameter diminution, and the increased production of reactive oxygen species (ROS) induced by TGF-ß1. Utilizing A779 inhibited the anti-atrophic effect of Ang-(1-7). CONCLUSION: The preventive effect of Ang-(1-7) on skeletal muscle atrophy induced by TGF-ß1 is produced through inhibition of ROS production and proteasomal degradation of MHC.


Assuntos
Angiotensina I/uso terapêutico , Atrofia Muscular/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Músculo Esquelético , Atrofia Muscular/patologia , Cadeias Pesadas de Miosina/metabolismo , Miosinas/metabolismo , Poliubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos
15.
Pain ; 157(12): 2709-2721, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27541850

RESUMO

Many cancerous solid tumors metastasize to the bone and induce pain (cancer-induced bone pain [CIBP]). Cancer-induced bone pain is often severe because of enhanced inflammation, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain, but they may enhance bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and bone integrity. Cancer inoculation increased spontaneous pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating pain.


Assuntos
Analgésicos/uso terapêutico , Angiotensina I/uso terapêutico , Neoplasias Ósseas/complicações , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Fragmentos de Peptídeos/uso terapêutico , Análise de Variância , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores do Receptor Tipo 2 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Imidazóis/uso terapêutico , Losartan/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Comportamento de Nidação/efeitos dos fármacos , Piridinas/uso terapêutico , Teste de Desempenho do Rota-Rod
16.
Expert Opin Ther Pat ; 26(6): 669-78, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27121991

RESUMO

INTRODUCTION: Angiotensin-(1-7) is a key component of the Renin-Angiotensin System, which can counter-regulate several deleterious effects caused by angiotensin II. Due to the potential for therapeutic use, several of its actions are specifically described in patents. AREAS COVERED: In this review, the authors describe a plethora of therapeutic uses for Angiotensin-(1-7), claimed and supported by experimental evidence in patent documents and applications. EXPERT OPINION: The clinical potential of Angiotensin-(1-7) as a therapeutic agent to treat several pathologies is evidenced by the variety of patents and clinical trials involving this peptide. Cancer treatment is one of the most advanced therapeutic areas, but clinical studies are also available in several other areas, such as cardiovascular, hematological, transplantation, surgical and medical procedures.


Assuntos
Angiotensina I/uso terapêutico , Ensaios Clínicos como Assunto , Fragmentos de Peptídeos/uso terapêutico , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Desenho de Drogas , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Patentes como Assunto , Fragmentos de Peptídeos/metabolismo
17.
Urology ; 94: 312.e1-8, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27125877

RESUMO

OBJECTIVE: To investigate whether exogenous angiotensin (Ang)-(1-7) administration can protect against the damaging consequences of testicular ischemia reperfusion (tIR) injury. MATERIALS AND METHODS: Eighteen male Sprague-Dawley rats were divided equally among the following 3 groups: sham, unilateral tIR injury (1 hour of ischemic treatment and 4 hours of reperfusion), and tIR + Ang-(1-7) (0.3 mg/kg). Testicular tissues obtained from the rats were evaluated for the expression of testicular angiotensin-converting enzyme (tACE), Ang-(1-7), and the Ang-(1-7)-specific receptor Mas by immunohistochemistry and enzyme-linked immunosorbent assay. Reduced spermatogenesis, induction of the caspase-8 pathway, and nitric oxide (NO) generation were assessed. The effects of tIR and Ang-(1-7) treatment on the PI3K/Akt antiapoptosis pathway were also investigated. RESULTS: Testicular morphological changes and reduced spermatogenesis associated with decreased expression of the tACE/Ang-(1-7)/Mas axis were observed during tIR. These effects were also accompanied by increased activity of caspase-3 and -8, downregulation of the survivin and BAD transcripts, and decreased NO formation. During tIR, PTEN expression was increased, leading to inactivation of the PI3K/Akt pathway. Acute treatment with Ang-(1-7) prior to reperfusion attenuated the tIR-induced damage described above. CONCLUSION: Expression of the tACE/Ang-(1-7)/Mas axis was downregulated during tIR. Administration of exogenous Ang-(1-7) prior to reperfusion rescued tACE and Mas expression and protected against germ cell apoptosis and oxidative stress. Increased NO generation and activation of the PI3K/Akt signaling pathway may have partially contributed to these effects. The tACE/Ang-(1-7)/Mas axis likely plays a role in the maintenance of normal testis physiology and spermatogenesis.


Assuntos
Angiotensina I/fisiologia , Angiotensina I/uso terapêutico , Fragmentos de Peptídeos/fisiologia , Fragmentos de Peptídeos/uso terapêutico , Peptidil Dipeptidase A/biossíntese , Traumatismo por Reperfusão/prevenção & controle , Testículo/irrigação sanguínea , Testículo/metabolismo , Animais , Masculino , Peptidil Dipeptidase A/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/fisiologia , Traumatismo por Reperfusão/etiologia
18.
Pharmacol Res ; 107: 372-380, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26956523

RESUMO

Congestive heart failure is one of the most prevalent and deadly complications of type 2 diabetes that is frequently associated with pulmonary dysfunction. Among many factors that contribute to development and progression of diabetic complications is angiotensin II (Ang2). Activation of pathological arm of renin-angiotensin system results in increased levels of Ang2 and signaling through angiotensin type 1 receptor. This pathway is well recognized for its role in induction of oxidative stress (OS), inflammation, hypertrophy and fibrosis. Angiotensin (1-7) [A(1-7)], through activation of Mas receptor, opposes the actions of Ang2 which can result in the amelioration of diabetic complications; enhancing the overall welfare of diabetic patients. In this study, 8 week-old db/db mice were administered A(1-7) daily via subcutaneous injections. After 16 weeks of treatment, echocardiographic assessment of heart function demonstrated significant improvement in cardiac output, stroke volume and shortening fraction in diabetic animals. A(1-7) also prevented cardiomyocyte hypertrophy, apoptosis, lipid accumulation, and decreased diabetes-induced fibrosis and OS in the heart tissue. Treatment with A(1-7) reduced levels of circulating proinflammatory cytokines that contribute to the low grade inflammation observed in diabetes. In addition, lung pathologies associated with type 2 diabetes, including fibrosis and congestion, were decreased with treatment. OS and macrophage infiltration were also reduced in the lungs after treatment with A(1-7). Long-term administration of A(1-7) to db/db mice is effective in improving heart and lung function in db/db mice. Treatment prevented pathological remodeling of the tissues and reduced OS, fibrosis and inflammation.


Assuntos
Angiotensina I/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Angiotensina I/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Fibrose , Coração/efeitos dos fármacos , Coração/fisiologia , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia
19.
Br J Pharmacol ; 173(10): 1618-28, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26895462

RESUMO

BACKGROUND AND PURPOSE: There is presently no proven pharmacological therapy for the acute respiratory distress syndrome. Recently, we and others discovered that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] shows significant beneficial effects in preclinical models of acute lung injury (ALI). Here, we aimed to identify the best time window for Ang-(1-7) administration to protect rats from oleic acid (OA) induced ALI. EXPERIMENTAL APPROACH: The effects of i.v. infused Ang-(1-7) were examined over four different time windows before or after induction of ALI in male Sprague-Dawley rats. Haemodynamic effects were continuously monitored, and loss of barrier function, inflammation and lung peptidase activities were measured as experimental endpoints. KEY RESULTS: Ang-(1-7) infusion provided the best protection against experimental ALI when administered by continuous infusion starting immediately after 30 min OA infusion till the end of the experiment (30-240 min). Both pretreatment (-60 to 0 min before OA) and short-term therapy (30-90 min) also had beneficial effects although less pronounced than the effects achieved with the optimal therapy window. Starting infusion of Ang-(1-7) 60 min after the end of OA treatment (90-240 min) did not protect barrier function or haemodynamics but still reduced myeloperoxidase activity and increased ACE2/ACE activity ratio respectively. CONCLUSIONS AND IMPLICATIONS: Our findings indicate that early initiation of therapy after ALI and continuous drug delivery are most beneficial for optimal therapeutic efficiency of Ang-(1-7) treatment in experimental ALI and, presumably accordingly, in clinical acute respiratory distress syndrome.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Angiotensina I/administração & dosagem , Angiotensina I/uso terapêutico , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Hemodinâmica/efeitos dos fármacos , Infusões Intravenosas , Masculino , Ácido Oleico , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
20.
Dis Model Mech ; 9(4): 441-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26851244

RESUMO

Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS) causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7) [Ang-(1-7)], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7) in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7) and the Mas receptor in disuse muscle atrophyin vivousing unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT) and Mas-knockout (Mas KO) mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7) immobilization-induced muscle atrophy. Our results found that Ang-(1-7) prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7) increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7) were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7) via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy.


Assuntos
Angiotensina I/uso terapêutico , Atrofia Muscular/tratamento farmacológico , Transtornos Musculares Atróficos/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Angiotensina I/farmacologia , Animais , Fator de Crescimento Insulin-Like I/metabolismo , Contração Isométrica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Força Muscular/efeitos dos fármacos , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Transtornos Musculares Atróficos/metabolismo , Transtornos Musculares Atróficos/patologia , Transtornos Musculares Atróficos/fisiopatologia , Cadeias Pesadas de Miosina/metabolismo , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
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