Assuntos
Cardiologia , Sistema Cardiovascular , Miocardite , Brasil , Humanos , Miocardite/diagnóstico , Miocardite/terapia , Sociedades MédicasRESUMO
The G protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor and is associated with angiotensin-(1-7) signaling. We investigated the effect of Mas-deficiency on blood pressure regulation under physiological conditions and salt load using radiotelemetry. Mas-knockout mice and their wild-type controls received a telemetry implant in the carotid artery. One week after surgery, animals were monitored for 3 days receiving normal diet (0.6% NaCl) followed by one-week high-salt diet (8% NaCl). Under same high-salt diet, another set of mice was placed in individual metabolic cages for 4 days. Basal mean arterial pressure, heart rate and locomotor activity displayed normal day-night rhythm in Mas-deficient mice. Mas-knockout mice were normotensive. High dietary NaCl ingestion did not alter heart rate or locomotor activity in both groups, but significantly increased night time mean arterial pressure in control mice whereas this increase was blunted in Mas-deficient mice. Baseline food and water intake and urine osmolality were not different between both genotypes. Under high-salt diet, water consumption and food intake were equally increased in wild-type controls and Mas-knockout, but urinary electrolytes and osmolality were significantly higher in Mas-knockout. Taken together, basal hemodynamic parameters are unchanged in Mas-knockout mice. In contrast to wild-type controls, telemetric mean arterial pressure measurement revealed salt resistance in Mas-deficient animals, probably due to their higher urinary NaCl excretion. This is the first direct proof that Mas blockade might be a new option in the treatment of salt-sensitive hypertension.
Assuntos
Deleção de Genes , Hipertensão/induzido quimicamente , Hipertensão/genética , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Pressão Sanguínea/genética , Feminino , Hipertensão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proto-Oncogene MasRESUMO
Dendritic cells (DC) are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes and initiate primary immune responses. Angiotensin II (AII) is involved in key events of the inflammatory response. Because our previous work implicated an effect of AII on differentiation and function of murine and human DC, we investigated the impact of AII type 1 receptor (AT(1)) deficiency on the phenotypical and functional properties of mouse DC in vitro and in vivo. Bone marrow (BM) cells isolated from mice lacking AII subtype 1a receptor (AT(1a)), AII subtype 1b receptor (AT(1b)), or both receptor isoforms and control littermates [wild type (WT)] were cultured for 7 days in the presence of recombinant mouse granulocyte/macrophage colony-stimulating factor to generate myeloid DC in vitro. Generation of CD11c(+) cells was less efficient in both AT(1a)- and AT(1b)-deficient BM cells than in WT BM cell cultures. Moreover, DC generated from AT(1)-deficient progenitors showed lower levels of expression of major histocompatibility complex II (MHC-II) and CD11c (p < 0.01) and a marked reduction in their allostimulatory activity (p < 0.01 or 0.001). Although AT(1)-deficient DC released comparable levels of interleukin (IL)-10 and IL-12p70 to WT DC, they produced significantly lower levels of tumor necrosis factor alpha (TNF-alpha) (p < 0.05). Remarkably, CD11c(+) cells isolated from the spleen of AT(1) knockout mice challenged with lipopolysaccharide in vivo up-regulated MHC-II, CD40, and CD80 as did WT, but released significantly lower levels of TNF-alpha (p < 0.01). These data provide clear evidence that AT(1) controls differentiation and functionality of DC and thus may have a crucial impact on inflammatory processes where local angiotensinergic systems are known to be activated.
Assuntos
Células Dendríticas/fisiologia , Receptor Tipo 1 de Angiotensina/genética , Animais , Western Blotting , Antígeno CD11c/metabolismo , Separação Celular , Citocinas/metabolismo , Células Dendríticas/ultraestrutura , Endocitose , Citometria de Fluxo , Genes MHC da Classe II/genética , Genótipo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/citologia , Linfócitos T/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Chagas' disease (CD) affects around 18 million people in Latin America. To determine the diagnostic and prognostic value of natriuretic peptides in patients with CD, we measured atrial (ANP) and brain natriuretic peptide (BNP), and compared the findings with other dilated cardiomyopathies (DCM). METHODS: Blood samples were obtained from 111 CD patients, 62 patients with DCM due to other causes, and 43 gender- and age-matched healthy subjects. The CD and DCM patients were subdivided according to their NYHA classification. Natriuretic peptide concentrations were determined by immunoradiometric assays. RESULTS: ANP and more pronounced BNP levels were increased in CD and DCM patients in relation to the NYHA class. Circulating BNP concentrations were higher in CD patients in NYHA classes I-II than in the corresponding DCM patients (p = 0.020). Importantly, ANP and BNP were already significantly elevated in CD patients without systolic ventricular dysfunction (p < or = 0.001). In CD patients, both peptides were highly correlated with echocardiographic parameters (p < 10(-14)). Both ANP and BNP had comparable ability to predict death or the necessity for heart transplant (p < 0.0001). CONCLUSION: Natriuretic peptide levels can be used as a marker of asymptomatic CD without ventricular dysfunction and thus could be an ideal tool to identify these patients for early therapy.
Assuntos
Fator Natriurético Atrial/sangue , Doença de Chagas/sangue , Peptídeo Natriurético Encefálico/sangue , Adulto , Biomarcadores/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Doença de Chagas/mortalidade , Doença de Chagas/fisiopatologia , Doença de Chagas/cirurgia , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Transplante de Coração/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Volume SistólicoRESUMO
The renin-angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2-8)], Ang IV [Ang-(3-8)], and Ang-(1-7) may also have important biological activities. Ang-(1-7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1-7) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1-7) after an acute water load. Ang-(1-7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1-7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1-7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.