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1.
Prog Mol Biol Transl Sci ; 194: 49-65, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36631200

RESUMO

The renin angiotensin system (RAS) plays a major role in blood pressure regulation and electrolyte homeostasis and is mainly composed by two axes mediating opposite effects. The pressor axis, constituted by angiotensin (Ang) II and the Ang II type 1 receptor (AT1R), exerts vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory actions, while the depressor/protective axis, represented by Ang-(1-7), its Mas receptor (MasR) and the Ang II type 2 receptor (AT2R), opposes the actions elicited by the pressor arm. The MasR belongs to the G protein-coupled receptor (GPCR) family. To avoid receptor overstimulation, GPCRs undergo internalization and trafficking into the cell after being stimulated. Then, the receptor may induce other signaling cascades or it may even interact with other receptors, generating distinct biological responses. Thus, control of a GPCR regarding space and time affects the specificity of the signals transduced by the receptor and the ultimate cellular response. The present chapter is focused on the signaling and trafficking pathways of MasR under physiological conditions and its participation in the pathogenesis of numerous brain diseases.


Assuntos
Endocitose , Proto-Oncogene Mas , Sistema Renina-Angiotensina , Humanos , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Pressão Sanguínea/fisiologia , Proto-Oncogene Mas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/fisiologia
2.
ACS Chem Neurosci ; 13(10): 1491-1504, 2022 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-35533351

RESUMO

Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Further, the DIZE-mediated activation of ACE2 led to increased tyrosine hydroxylase (TH) and dopamine transporters (DAT) expression in the rat brain, indicating the protection of dopaminergic (DAergic) neurons from 6-OHDA induced neurotoxicity. Moreover, 6-OHDA induced activation of glial cells (astrocytes and microglia) and release of neuroinflammatory mediators were attenuated by DIZE treatment in both in vitro as well as in vivo models of PD. DIZE exerted its effect by activating ACE2 that produced Ang (1-7), a neuroprotective peptide. Ang (1-7) conferred its neuroprotective effect upon binding with the G-protein-coupled MAS receptor that led to the upregulation of cell survival proteins while downregulating apoptotic proteins. Importantly, these findings were further validated by using A-779, a MasR antagonist. The result showed that treatment with A-779 reversed the antioxidative and anti-inflammatory effects of DIZE by decreasing glial activation and neuroinflammatory markers. Although the role of ACE2 in PD pathology needs to be additionally confirmed using transgenic models in either ACE2 overexpressing or knockout mice, still, our study demonstrates that enhancing ACE2 activity could be a novel approach for ameliorating PD pathology.


Assuntos
Enzima de Conversão de Angiotensina 2 , Diminazena/análogos & derivados , Doença de Parkinson , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Diminazena/farmacologia , Camundongos , Modelos Teóricos , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proto-Oncogene Mas/metabolismo , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Eur Rev Med Pharmacol Sci ; 26(6): 1852-1859, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35363333

RESUMO

OBJECTIVE: Angiotensin-converting enzyme 2(ACE2) is a critical element of the renin-angiotensin system (RAS), which can convert angiotensin (Ang)II to Ang(1-7), followed by binding Mas receptor (MasR) and subsequently produces cardioprotective effects through various signal transduction pathways. It has been discovered in research that activation of the RAS contributes a crucial influence during the myocardial ischemia reperfusion injury (MIRI) development. The features of ACE2, Ang(1-7), and MasR, as well as the function of the ACE2/Ang(1-7)/MasR axis in MIRI, are discussed in our review, with the therapeutic potential of this axis as a new treatment option for MIRI patients shown. MATERIALS AND METHODS: To retrieve a thorough collection of studies, we performed a search in PubMed using the following combination of keywords: (ACE2) or (Ang1-7) or (Mas receptor) and (Myocardial Ischemia reperfusion injury). The time limits used for the search were 1986 to 2021. RESULTS: In total, 367 articles were included. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included. CONCLUSIONS: ACE2, a prominent member of the RAS, performs a crucial regulatory function in the cardiovascular system. ACE2 regulates the RAS inversely mainly by hydrolyzing the harmful AngII to the beneficial Ang(1-7). Increasing or activating ACE2 or Ang(1-7) may help prevent and treat MIRI. However, additional research into the specific processes behind the ACE2/Ang(1-7)/MasR axis in MIRI is necessary, as well as the performance of additional in-depth studies to go from basic research to clinical translation.


Assuntos
Enzima de Conversão de Angiotensina 2 , Traumatismo por Reperfusão Miocárdica , Proto-Oncogene Mas , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proto-Oncogene Mas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/fisiologia
4.
Int J Mol Sci ; 23(6)2022 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-35328506

RESUMO

Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1-7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Inflamassomos/metabolismo , AVC Isquêmico/metabolismo , Doenças Neuroinflamatórias/metabolismo , Proteínas/metabolismo , Angiotensina I/metabolismo , COVID-19/complicações , COVID-19/virologia , Humanos , AVC Isquêmico/complicações , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuroinflamatórias/complicações , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Transdução de Sinais
5.
Mol Cell Biochem ; 477(1): 225-240, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34655418

RESUMO

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.


Assuntos
Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/dietoterapia , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/virologia , Proteínas Alimentares/farmacologia , Flavonoides/farmacologia , Humanos , Pulmão/patologia , Pulmão/virologia , Óleos de Plantas/farmacologia , Polifenóis/farmacologia , Terpenos/farmacologia , Internalização do Vírus , Vitaminas/farmacologia
6.
JCI Insight ; 7(1)2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34874920

RESUMO

Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.


Assuntos
Angiotensina I , Macrófagos , Monócitos , Fragmentos de Peptídeos , Fagocitose , Proto-Oncogene Mas/metabolismo , Angiotensina I/metabolismo , Angiotensina I/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peritonite , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Fenótipo , Receptores CCR2/metabolismo
7.
Sci Rep ; 11(1): 24397, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34937861

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is an important factor in coronavirus disease (COVID-19) interactions. Losartan (LOS) belongs to the angiotensin receptor blocker (ARB) family. Additionally, the protective role of ACE2 restored by LOS has been suggested and clinically examined in the treatment of COVID-19 patients. Furthermore, clinical trials with LOS have been conducted. However, the mechanism through which LOS enhances ACE2 expression remains unclear. In addition, the response of ACE2 to LOS differs among patients. Our LOS-treated patient data revealed a correlated mechanism of ACE2 with components of the renin-angiotensinogen system. We observed a significant positive regulation of MAS1 and ACE2 expression. In the context of LOS treatment of COVID-19, ACE2 expression could depend on LOS regulated MAS1. Thus, MAS1 expression could predict the COVID-19 treatment response of LOS.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , Losartan/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/genética , COVID-19/patologia , COVID-19/virologia , Bases de Dados Factuais , Humanos , Losartan/uso terapêutico , Proto-Oncogene Mas/genética , Proto-Oncogene Mas/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , SARS-CoV-2/isolamento & purificação , Regulação para Cima/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
8.
Biomolecules ; 11(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944506

RESUMO

Renin-angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion-reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood-brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion-reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion-reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.


Assuntos
Angiotensina II/administração & dosagem , Angiotensina I/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Pia-Máter/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Tetrazóis/administração & dosagem , Angiotensina I/efeitos adversos , Angiotensina II/efeitos adversos , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Feminino , Masculino , Microcirculação/efeitos dos fármacos , Microscopia de Fluorescência , Fragmentos de Peptídeos/efeitos adversos , Pia-Máter/efeitos dos fármacos , Pia-Máter/metabolismo , Proto-Oncogene Mas/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Tetrazóis/farmacologia
9.
Int J Mol Sci ; 22(24)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34948475

RESUMO

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure.


Assuntos
Angiotensina II/administração & dosagem , Angiotensina I/administração & dosagem , Cardiomegalia/prevenção & controle , Hipertensão/tratamento farmacológico , Imidazóis/administração & dosagem , Losartan/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Fibrose , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Imidazóis/farmacologia , Injeções Intraperitoneais , Losartan/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Proto-Oncogene Mas/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo
10.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34884756

RESUMO

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1-7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1-7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.


Assuntos
Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Fibrose/metabolismo , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas/metabolismo , Cannabis , Fumar Cigarros , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Inflamação , Pulmão/patologia , Pandemias , Respiração Artificial , Síndrome do Desconforto Respiratório , Insuficiência Respiratória/metabolismo , Fatores de Risco , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
11.
J Mol Endocrinol ; 68(2): 77-87, 2021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34825653

RESUMO

20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysteroid receptors (EcR/RXR complex) and at least one membrane GPCR receptor (DopEcR). It also displays numerous pharmacological effects in mammals, where its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERß receptor. The goal of this study was to better understand 20E mechanism of action in mammals. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) were used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with angiotensin(1-7), the endogenous ligand of MAS. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using siRNA or pharmacological inhibitors. 17ß-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin(1-7) antagonists. A mechanism involving cooperation between the MAS receptor and a membrane-bound palmitoylated estrogen receptor is proposed. The possibility to activate the MAS receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and, indeed, the proposed mechanism may explain the close similarity between the effects of angiotensin(1-7) and 20E. Our findings open up many possible therapeutic developments involving stimulation of the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.


Assuntos
Ecdisterona/metabolismo , Proto-Oncogene Mas/metabolismo , Sistema Renina-Angiotensina , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ecdisterona/química , Ecdisterona/farmacologia , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica , Camundongos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Ligação Proteica , Proto-Oncogene Mas/agonistas , Proto-Oncogene Mas/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Esteroides/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
12.
Mol Biol Rep ; 48(12): 8033-8044, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34743271

RESUMO

BACKGROUND: The imbalance of vasoconstrictor and vasodilator axes of the renin-angiotensin system (RAS) is observed in hypertension. Exercise regulates RAS level and improves vascular function. This study focused on the contribution of RAS axes in vascular function of mesenteric arteries and exercise-induced DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in hypertension. METHODS: Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were randomized into exercise or sedentary group. Levels of plasma RAS components, vascular tone, and DNA methylation markers were measured. RESULTS: Blood pressure of SHR was markedly reduced after 12 weeks of aerobic exercise. RAS peptides in plasma were all increased with an imbalanced upregulation of Ang II and Ang-(1-7) in SHR, exercise revised the level of RAS and increased Ang-(1-7)/Ang II. The vasoconstriction response induced by Ang II was mainly via type 1 receptors (AT1R), while this contraction was inhibited by Mas receptor (MasR). mRNA and protein of AT1R and MasR were both upregulated in SHR, whereas exercise significantly suppressed this imbalanced increase and increased MasR/AT1R ratio. Exercise hypermethylated Agtr1a and Mas1 genes, associating with increased DNMT1 and DNMT3b and SAM/SAH. CONCLUSIONS: Aerobic exercise ameliorates vascular function via hypermethylation of the Agtr1a and Mas1 genes and restores the vasoconstrictor and vasodilator axes balance.


Assuntos
Proto-Oncogene Mas/metabolismo , Hipertensão Arterial Pulmonar/terapia , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/metabolismo , Animais , Artérias/metabolismo , Pressão Sanguínea/efeitos dos fármacos , DNA/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Hipertensão/metabolismo , Masculino , Artérias Mesentéricas/fisiologia , Óxido Nítrico/metabolismo , Condicionamento Físico Animal/métodos , Esforço Físico/genética , Esforço Físico/fisiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
13.
Pharmacol Res ; 174: 105924, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34607005

RESUMO

Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT2) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT2 receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF.


Assuntos
Pulmão/metabolismo , Fibrose Pulmonar/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antifibróticos/uso terapêutico , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Terapia de Alvo Molecular , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Transdução de Sinais
14.
Mol Biol Rep ; 48(9): 6619-6629, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34417705

RESUMO

BACKGROUND: In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved in the pathogenesis of RA and OA. The aim of this mini-review article is to summarize evidence on the role of RAS in RA and OA. METHODS: A non-systematic search in Pubmed included terms as "rheumatoid arthritis", "renin angiotensin system", "osteopenia", "RANKL", "DKK-1", "MMP", "inflammation", "angiogenesis", "local renin-angiotensin system", "angiotensin converting enzyme", "AT2 receptor", "Ang-(1-7)", "VEGF", "angiotensine receptor blocker", "angiotensin converting enzyme inhibitors", "renin inhibitors". RESULTS: Both RAS axes, the classical one, formed by angiotensin converting enzyme (ACE), angiotensin (Ang) II and AT1 receptor (AT1R) and the counter-regulatory one, composed by ACE2, Ang-(1-7) and the Mas receptor, modulate inflammation and tissue damage. Ang II activates pro-inflammatory mediators and oxidative stress. Conversely, Ang-(1-7) exerts anti-inflammatory actions, decreasing cytokine release, leukocyte attraction, density of vessels, tissue damage and fibrosis. Angiogenesis facilitates inflammatory cells invasion, while osteopenia causes joint dysfunction. Up-regulated osteoclastogenisis and down-regulated osteoblastogeneses were associaed with the activation of the classical RAS axis. Three different pathways, RANKL, DKK-1 and MMPs are enhanced by classical RAS activation. The treatment of RA included methotrexate and corticosteroids, which can cause side effects. Studies with angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEi) and renin inhibitors have been conducted in experimental and clinical RA with promising results. CONCLUSION: The classical RAS activation is an important mechanism in RA pathogenesis and the benefit of ARB and ACEi administration should be further investigated.


Assuntos
Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Sistema Renina-Angiotensina , Corticosteroides/uso terapêutico , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Humanos , Osteoartrite/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proto-Oncogene Mas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
15.
J Cardiovasc Pharmacol ; 78(1): e55-e64, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232225

RESUMO

ABSTRACT: Left ventricular hypertrophy (LVH) makes the heart vulnerable to ischemia/reperfusion (IR) injury. Angiotensin (Ang) (1-7) is recognized as a cardioprotective peptide. We investigated the effect of polyphenol resveratrol on myocardial IR injury after hypertrophy and examined cardiac content of Ang (1-7) and transcription of its receptor (MasR). Rats were divided into sham-operated, LVH, IR, LVH + IR, and resveratrol + LVH + IR groups. Myocardial hypertrophy and IR models were created by abdominal aortic banding and left coronary artery occlusion, respectively. To evaluate the electrocardiogram parameters and incidence of arrhythmias, electrocardiogram was recorded by subcutaneous leads (lead II). Blood pressure was measured through the left carotid artery. Infarct size was determined by the triphenyl tetrazolium chloride staining. The Ang (1-7) level was evaluated by immunohistochemistry. The Mas receptor mRNA level was assessed by the real-time real time reverse transcription polymerase chain reaction technique. QT-interval duration, infarct size, and incidence of ischemia-induced arrhythmia were significantly higher in the LVH + IR group. However, in the resveratrol-treated group, these parameters were decreased significantly. The cardiac level of Ang (1-7) was decreased in untreated hypertrophied hearts (LVH and LVH + IR groups). Pretreatment with resveratrol normalized the cardiac level of Ang (1-7). The mRNA level of Mas receptor was increased in all of hypertrophied hearts in the presence or absence of resveratrol. Resveratrol can decrease IR injury in rats with LVH. The anti-ischemic effect of resveratrol may be related to the enhancement of Ang (1-7)/MasR axis.


Assuntos
Angiotensina I/metabolismo , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas/metabolismo , Resveratrol/farmacologia , Animais , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Proto-Oncogene Mas/genética , Ratos Wistar , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/prevenção & controle
16.
Peptides ; 144: 170612, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298021

RESUMO

Sepsis-induced myocardial dysfunction is a major cause of death. The present study explored whether angiotensin (Ang)-(1-7), an important biologically active peptide of the renin-angiotensin system, could improve cardiac dysfunction and attenuate inflammation and apoptosis. Experiments were carried out in mice and in neonatal rat cardiomyocytes (NRCMs) treated with lipopolysaccharide (LPS) or Ang-(1-7). Angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and Mas receptor (MasR) expressions were reduced in the mouse left ventricular and NRCM treated with LPS. Ang-(1-7) increased the ejection fraction and fractional shortening of left ventricular, which were reduced upon LPS injection in mice. Ang-(1-7) pre-treatment reversed LPS-induced decreases of α-myosin heavy chain (MHC) and ß-MHC, and increases of S100 calcium binding protein A8 (S100A8) and S100A9 in the mouse left ventricular. The LPS-induced increases of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the mouse left ventricular and NRCMs were inhibited by Ang-(1-7) administration. Ang-(1-7) treatment reversed the increases of cleaved-caspase 3, cleaved-caspase 8 and Bax, and the decrease of Bcl2 induced by LPS in the mouse left ventricular and NRCMs. The increases of MAPKs pathway induced by LPS in NRCMs were inhibited by Ang-(1-7). These results indicate that Ang-(1-7) protects against sepsis-associated left ventricular dysfunction induced by LPS, and increases cardiac contractility via attenuating inflammation and apoptosis.


Assuntos
Angiotensina I/farmacologia , Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sepse/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas/antagonistas & inibidores , Proto-Oncogene Mas/metabolismo , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Sepse/induzido quimicamente , Disfunção Ventricular Esquerda/etiologia
17.
Cancer Lett ; 519: 130-140, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34216689

RESUMO

The Mas receptor has been reported to promote migration and invasion of clear cell renal cell carcinoma (ccRCC) cells via Ang-(1-7)-dependent AKT signaling. However, the mechanism underlying the regulation of Mas function remains unknown. Here, eight PDZ domain-containing proteins were identified as Mas interactors using surface plasmon resonance (SPR) coupled to mass spectrometry (MS). NHERF4 was the only downregulated gene across multiple independent ccRCC datasets. GST pull-down and co-immunoprecipitation assays confirmed physical interaction between NHERF4 and Mas. Using NHERF4 overexpression and knockdown assays, we found that NHERF4 inhibited Mas-induced migration, invasion and in vivo metastasis of ccRCC cells. Mechanistically, NHERF4 suppressed Mas-stimulated AKT phosphorylation and the PLC/Ca2+ response. We further demonstrated that NHERF4 compromised Mas-mediated migration and invasion of ccRCC cells via regulation of the PLC/AKT signaling axis. Analysis of the ccRCC dataset revealed that low levels of NHERF4 expression were correlated with higher TNM stage, and independently predicted poor prognosis of ccRCC patients. Overall, our study identified NHERF4 as a novel regulator of ccRCC invasiveness, and a prognostic biomarker, which may be beneficial for determining optimal therapeutic strategies for ccRCC patients.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Fosfoproteínas/metabolismo , Proto-Oncogene Mas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Células COS , Carcinoma de Células Renais/patologia , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Células HEK293 , Humanos , Neoplasias Renais/patologia , Fosforilação/fisiologia
18.
J Cardiovasc Pharmacol ; 78(1): e65-e76, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33929390

RESUMO

ABSTRACT: There is increasing evidence that angiotensin (1-7) [Ang (1-7)] is an endogenous biologically active component of the renin-angiotensin system. However, the role of the Ang (1-7)-MasR axis in postresuscitation myocardial dysfunction (PRMD) and its associated mechanism are still unclear. In this study, we investigated the effect of the Ang (1-7)-MasR axis on myocardial injury after cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation. We established a model of oxygen/glucose deprivation-reperfusion in myocardial cells in vitro and a rat model of cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation in vivo. The cell apoptosis rate and the expression of the superoxide anion 3-nitrotyrosine were decreased in the Ang (1-7) group in vitro and in vivo. The mean arterial pressure was decreased, whereas +LVdp/dtmax and -LVdp/dtmax were increased in rats in the Ang (1-7) group. The mRNA and protein levels of Ang II type 1 receptor, MasR, phosphoinositide 3-kinase, protein kinase B, and endothelial nitric oxide synthase were increased in the Ang (1-7) group in vivo. These results indicate that the Ang (1-7)-MasR axis can alleviate PRMD by reducing myocardial tissue damage and oxidative stress through activation of the phosphoinositide 3-kinase-protein kinase B-endothelial nitric oxide synthase signaling pathway and provide a new direction for the clinical treatment of PRMD.


Assuntos
Angiotensina I/farmacologia , Reanimação Cardiopulmonar/efeitos adversos , Parada Cardíaca/terapia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Parada Cardíaca/fisiopatologia , Cardiopatias/enzimologia , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Masculino , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Proto-Oncogene Mas/agonistas , Proto-Oncogene Mas/genética , Proto-Oncogene Mas/metabolismo , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Retorno da Circulação Espontânea , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos
20.
Neurotherapeutics ; 18(2): 998-1016, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33474655

RESUMO

The renin-angiotensin system (RAS) not only plays an important role in controlling blood pressure but also participates in almost every process to maintain homeostasis in mammals. Interest has recently increased because SARS viruses use one RAS component (ACE2) as a target-cell receptor. The occurrence of RAS in the basal ganglia suggests that the system may be targeted to improve the therapy of neurodegenerative diseases. RAS-related data led to the hypothesis that RAS receptors may interact with each other. The aim of this paper was to find heteromers formed by Mas and angiotensin receptors and to address their functionality in neurons and microglia. Novel interactions were discovered by using resonance energy transfer techniques. The functionality of individual and interacting receptors was assayed by measuring levels of the second messengers cAMP and Ca2+ in transfected human embryonic kidney cells (HEK-293T) and primary cultures of striatal cells. Receptor complex expression was assayed by in situ proximity ligation assay. Functionality and expression were assayed in parallel in primary cultures of microglia treated or not with lipopolysaccharide and interferon-γ (IFN-γ). The proximity ligation assay was used to assess heteromer expression in parkinsonian and dyskinetic conditions. Complexes formed by Mas and the angiotensin AT1 or AT2 receptors were identified in both a heterologous expression system and in neural primary cultures. In the heterologous system, we showed that the three receptors-MasR, AT1R, and AT2R-can interact to form heterotrimers. The expression of receptor dimers (AT1R-MasR or AT2R-MasR) was higher in microglia than in neurons and was differentially affected upon microglial activation with lipopolysaccharide and IFN-γ. In all cases, agonist-induced signaling was reduced upon coactivation, and in some cases just by coexpression. Also, the blockade of signaling of two receptors in a complex by the action of a given (selective) receptor antagonist (cross-antagonism) was often observed. Differential expression of the complexes was observed in the striatum under parkinsonian conditions and especially in animals rendered dyskinetic by levodopa treatment. The negative modulation of calcium mobilization (mediated by AT1R activation), the multiplicity of possibilities on RAS affecting the MAPK pathway, and the disbalanced expression of heteromers in dyskinesia yield new insight into the operation of the RAS system, how it becomes unbalanced, and how a disbalanced RAS can be rebalanced. Furthermore, RAS components in activated microglia warrant attention in drug-development approaches to address neurodegeneration.


Assuntos
Microglia/metabolismo , Transtornos Parkinsonianos/metabolismo , Proto-Oncogene Mas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Proto-Oncogene Mas/agonistas , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/agonistas , Sistema Renina-Angiotensina/efeitos dos fármacos
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