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Objective: The present study aims to investigate the relationship between vitamin D deficiency and renin-angiotensin-aldosterone levels in patients with essential hypertension. Methods: The present study observed two groups of patients from Urumqi, Xinjiang, China, from April 2017 to March 2018. There were two subject groups: the hypertension group (80 patients with essential hypertension selected by random cluster sampling) and the control group (76 healthy adults). The 25-hydroxyvitamin D (25(OH)D or vitamin D) levels were measured through electrolytes; fasting blood glucose, blood lipids, and other biochemical indicators were detected using immune chemiluminescence; and plasma renin activity and angiotensin II concentrations were detected with radio-immunity. Results: Comparison between the hypertension group and control group showed statistically significant differences in the systolic pressure and levels of 25(OH)D, renin, and triglycerides (P < 0.05). The correlation analysis showed that 25(OH)D was negatively correlated with renin (r = -0.185; P=0.021) and positively correlated with systolic pressure (r = -0.105; P=0.035). There were no statistically significant differences in diastolic pressure, fasting blood glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides between the two groups. Conclusions: The results of the present study show that vitamin D deficiency is common in Urumqi, Xinjiang, China and vitamin D levels are negatively correlated with renin levels. Vitamin D plays an important role in regulating blood pressure by affecting renin levels through the renin-angiotensin-aldosterone system.
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Angiotensinas , Hipertensión Esencial , Renina , Deficiencia de Vitamina D , Adulto , Aldosterona/sangre , Angiotensinas/sangre , Pueblo Asiatico , Presión Sanguínea , Hipertensión Esencial/sangre , Hipertensión Esencial/complicaciones , Hipertensión Esencial/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Renina/sangre , Deficiencia de Vitamina D/complicacionesRESUMEN
BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.
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Biomarcadores/sangre , COVID-19/complicaciones , Hospitalización , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/diagnóstico , Insuficiencia Respiratoria/complicaciones , Insuficiencia Respiratoria/diagnóstico , Caracteres Sexuales , Adulto , Enzima Convertidora de Angiotensina 2/sangre , Angiotensinas/sangre , COVID-19/sangre , Estradiol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/sangre , Insuficiencia Respiratoria/sangre , SARS-CoV-2 , Testosterona/sangreRESUMEN
Angiotensin (Ang) peptides are the main effectors of the renin-angiotensin system (RAS) regulating diverse physiological conditions and are involved in renal and vascular diseases. Currently, quantitative analyses of Ang peptides in human plasma mainly rely on radioimmunoassay-based methods whose reported levels are quite divergent. Analyses are further complicated by the potential of Ang peptides to bind to solid surfaces, to be enzymatically decomposed during sample preparation, and to undergo post-translational modifications. A column switching-parallel LC/ESI-SRM/MS method has been developed for seven Ang peptides (Ang I, Ang II, Ang III, Ang IV, Ang 1-9, Ang 1-7, and Ang A) in human plasma. Aqueous acetonitrile (5%) containing 50 mM arginine (Arg) as a dissolving solution and a combination of protease inhibitors with formic acid were used to prevent adsorption and enzymatic degradation, respectively. Plasma samples were simply deproteinized with acetonitrile followed by clean-up with an on-line trap column via column-switching. Stable isotope dilution with [13C5,15N1-Val]-Ang peptides as internal standards was employed for quantitative analysis. The current methodology has been successfully applied to determine the plasma levels of Ang peptides in healthy participants, suggesting future applicability to studies of various diseases related to RAS.
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Angiotensinas/sangre , Análisis Químico de la Sangre , Péptidos/sangre , Adulto , Cromatografía Liquida , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Espectrometría de Masa por Ionización de Electrospray , Adulto JovenRESUMEN
[Figure: see text].
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Angiotensinas/sangre , Leptina/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Sistema Renina-Angiotensina/fisiología , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Femenino , Humanos , Leptina/farmacología , Leucil Aminopeptidasa/metabolismo , Placenta/efectos de los fármacos , Placenta/fisiopatología , Preeclampsia/fisiopatología , Embarazo , Sistema Renina-Angiotensina/efectos de los fármacos , Tetrazoles/farmacología , Arteria Uterina/fisiopatología , Resistencia Vascular/fisiologíaAsunto(s)
Infecciones por Coronavirus/patología , Peptidil-Dipeptidasa A/genética , Neumonía Viral/patología , Serina Endopeptidasas/genética , Acoplamiento Viral , Internalización del Virus , Envejecimiento , Enzima Convertidora de Angiotensina 2 , Angiotensinas/sangre , Apelina/sangre , Betacoronavirus , Bradiquinina/sangre , COVID-19 , Catepsina B/metabolismo , Catepsina L/metabolismo , Humanos , Miocardio/patología , Miocitos Cardíacos/metabolismo , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: To investigate the relationships of plasma renin, angiotensin, and aldosterone levels to blood pressure variability and target organ damage in children with essential hypertension. METHODS: A case-control study was conducted on 132 children diagnosed with essential hypertension (103 males and 29 females with the mean age of 11.8 ± 2.4 years). The plasma RAAS levels were measured using the enhanced chemiluminescence method, the ambulatory blood pressure was monitored for 24 h, and then the average real variability (ARV) was calculated. Data on indicators were used for assessing cardiac and renal damages. The correlations of plasma renin, angiotensin, and aldosterone (RAAS) levels to blood pressure variability (BPV) and target organ damage (TOD) were studied. A comparison between the groups was conducted using SPSS 20. RESULTS: Among the 132 children, 55 cases had target organ damage. The 24-h ARV and the daytime ARV of the systolic blood pressure of the high angiotensin II (AT II) group was significantly higher than that of the normal AT II group (t = 2.175, P = 0.031; t = 2.672, P = 0.009). Plasma AT II and aldosterone levels were significantly associated with the left ventricular mass index (r = 0.329, P = 0.0001; r = 0.175, P = 0.045). Linear regression analysis showed that AT II [ß ± s.e. = 0.025 ± 0.006, 95% CI (0.013-0.038), P = 0.0001] and aldosterone [ß ± s.e. = 0.021 ± 0.007, 95% CI (0.008-0.034), P = 0.002] were risk factors for LVH. CONCLUSIONS: The AT II level in children with essential hypertension affected the variability of the 24-h and the daytime SBP. Plasma AT II and aldosterone levels were associated with cardiac damage. Results from this study indicated that AT II and aldosterone are risk factors for LVH in childhood hypertension and are of great significance for improving the clinical prognosis of pediatric patients with hypertension.
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Aldosterona/sangre , Angiotensinas/sangre , Presión Sanguínea , Hipertensión Esencial/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Enfermedades Renales/etiología , Sistema Renina-Angiotensina , Renina/sangre , Adolescente , Factores de Edad , Biomarcadores/sangre , Niño , Hipertensión Esencial/sangre , Hipertensión Esencial/diagnóstico , Hipertensión Esencial/fisiopatología , Femenino , Humanos , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/fisiopatología , Enfermedades Renales/sangre , Enfermedades Renales/diagnóstico , Enfermedades Renales/fisiopatología , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. METHODS: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. RESULTS: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. CONCLUSION: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.
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Apoptosis , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/patología , Transducción de Señal , Volumen Sistólico , Quinasas Asociadas a rho/metabolismo , Angiotensinas/sangre , Animales , Antígenos CD/metabolismo , Catecolaminas/sangre , Citocinas/sangre , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Humanos , Janus Quinasa 2/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Persona de Mediana Edad , Miocardio/patología , Fosfatasa de Miosina de Cadena Ligera/metabolismo , Péptido Natriurético Encefálico/sangre , Fosforilación , Ratas , Sístole , Remodelación VentricularRESUMEN
Kir5.1 (encoded by the Kcnj16 gene) is an inwardly rectifying K+ (Kir) channel highly expressed in the aldosterone-sensitive distal nephron of the kidney, where it forms a functional channel with Kir4.1. Kir4.1/Kir5.1 channels are responsible for setting the transepithelial voltage in the distal nephron and collecting ducts and are thereby major determinants of fluid and electrolyte distribution. These channels contribute to renal blood pressure control and have been implicated in salt-sensitive hypertension. However, mechanisms pertaining to the impact of K ir4.1/Kir5.1-mediated K+ transport on the renin-angiotensin-aldosterone system (RAAS) remain unclear. Herein, we utilized a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) to investigate the relationship between Kir5.1 and RAAS balance and function in the sensitivity of blood pressure to the dietary Na+/K+ ratio. The knockout of Kcnj16 caused substantial elevations in plasma RAAS hormones (aldosterone and angiotensin peptides) and altered the RAAS response to changing the dietary Na+/K+ ratio. Blocking aldosterone with spironolactone caused rapid mortality in SSKcnj16-/- rats. Supplementation of the diet with high K+ was protective against mortality resulting from aldosterone-mediated mechanisms. Captopril and losartan treatment had no effect on the survival of SSKcnj16-/- rats. However, neither of these drugs prevented mortality of SSKcnj16-/- rats when switched to high Na+ diet. These studies revealed that the knockout of Kcnj16 markedly altered RAAS regulation and function, suggesting Kir5.1 as a key regulator of the RAAS, particularly when exposed to changes in dietary sodium and potassium content.
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Túbulos Renales Distales/metabolismo , Canales de Potasio de Rectificación Interna/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Aldosterona/sangre , Angiotensinas/sangre , Animales , Presión Sanguínea , Técnicas de Inactivación de Genes , Antagonistas de Receptores de Mineralocorticoides/farmacología , Potasio en la Dieta/administración & dosificación , Ratas Endogámicas Dahl , Sodio en la Dieta/administración & dosificación , Espironolactona/farmacología , Canal Kir5.1RESUMEN
At some works, it has been shown there are signs of damage and endothelium dysfunction in patients with chronic viral hepatitis (CVH) and liver cirrhosis of viral etiology the severity of these conditions depends on the severity of the pathological process. Evaluation of the role of angiogenic factors and endothelial dysfunction in persistent of CVH in children and adolescents. 35 patients were examined: of which 11 with chronic hepatitis B (CHB) and 24 with chronic hepatitis C (CHC). The reference group consisted of 120 practically healthy persons of the corresponding age and sex. VEGF-A, angiotensin (ANG), soluble receptors of VEGF-A (sVEGF-R1 и sVEGF-R2) and trombomodulin (TM) have been investigated in serum by enzyme immunoassay using special kits (BCM Diagnostics, USA). Other endothelial dysfunction markers as von Willebrand factor (vWf) was determined in blood plasma by immunoturbidimetry (Siemens, Germany), plasminogen (PLG) was investigated due to extended coagulation. In children with CVH, regardless of etiology, the concentration of VEGF-A was significantly lower, and sVEGF-R2, sVEGF-R1 and TM was higher than in children without liver disease (p <0.001, p <0.05, p <0.01, p <0.001, respectively). The concentration of TM and the level of PLG activity in patients with CHC were slightly higher than in CHB. Decreased level of VEGF-A and increased expression of its soluble receptors indicate enhanced inhibition of angiogenesis in CVH, which may indicate the pathogenetic role of this phenomenon in the development of liver damage in CHC.
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Hepatitis B Crónica/sangre , Hepatitis C Crónica/sangre , Cirrosis Hepática/virología , Neovascularización Patológica/sangre , Adolescente , Angiotensinas/sangre , Biomarcadores/sangre , Niño , Humanos , Plasminógeno/análisis , Trombomodulina/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Factor de von Willebrand/análisisRESUMEN
RESUMEN: Introducción: La vía clásica del sistema renina-angiotensina (SRA) está activado en pacientes con hipertensión arterial pulmonar (HAP). Previamente, hemos encontrado que en la disfunción ventricular post infarto al miocardio experimental la activación del eje clásico del SRA, dado por la enzima convertidora de angiotensina I (ECA) y angiotensina (Ang ) II se correlaciona negativamente con el eje paralelo del SRA dado por la ECA homóloga (ECA2) y el péptido vasoactivo y cardioprotector Ang-(1-9). Resultados preclínicos muestran la eficacia de la administración de Ang-(1-9) en el tratamiento del remodelamiento cardiovascular patológico. Hasta la fecha no existen antecedentes de los niveles circulantes de Ang-(1-9) en pacientes con hipertensión arterial pulmonar comparados con sujetos sanos. Objetivo: Determinar los niveles circulantes del péptido vasoactivo y cardiprotector Ang-(1-9) en pacientes con HAP y compararlos con sujetos sanos pareados por edad y sexo. Métodos: Estudio comparativo transversal en pacientes con HAP (grupo I, OMS) con presión de arteria pulmonar media (mPAP) ≥25 mmHg bajo tratamiento con furosemida (40%), espironolactona (53%), Acenocumarol/Warfarina (47%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) y digoxina (13%). Los sujetos controles correspondieron a sujetos asintomáticos sanos sin enfermedad cardiovascular, cardiopatía estructural ni pulmonar (n=14). En todos los pacientes se determinó mPAP, proBNP, resistencia vascular pulmonar (RVP, WU), presión capilar pulmonar (PCP, mmHg), gasto cardíaco (L/min), capacidad funcional por test de caminata 6 minutos (TC6M), cambio del área fraccional del ventrículo derecho VD (FAC, %). Se utilizó prueba t de Student y programa estadístico SPSS10.0. Un valor de p < 0,05 fue considerado como estadísticamente significativo. Resultados: Los pacientes ingresados al estudio mostraron: etiología de la HAP, idiopática (86,7%), VIH (13,3%), capacidad funcional I (6,2%), II (68,3) y III (25%) y promedio mPAP 51,3±1,9. Pacientes con HAP (grupo I, OMS) versus sujetos sanos mostraron disminución significativa de FAC, actividad plasmática de la ECA2 y niveles circulantes de Ang-(1-9). En la vía clásica del RAAS pacientes con HAP mostraron mayor actividad plasmática de ECA y niveles circulantes e Ag II. Correlaciones significativas se encontraron entre niveles de Ang-(1-9) y mPAP (r = -0.701, p < 0,001) y Ang-(1-9) vs FAC (r = 0.549, p < 0,01). Conclusiones: En pacientes con HAP (grupo I, OMS), los niveles circulantes de Ang-(1-9) están significativamente disminuidos y se asocian inversamente con la PAP, severidad del remodelamiento y disfunción del ventrículo derecho. El uso terapéutico de Ang-(1-9) como agente vasodilatador y cardioprotector podría ser relevante y potencialmente útil, desde una perspectiva clínica, en la HAP. Ang-(1-9) podría reducir la PAP y mejorar el remodelamiento vascular y del ventrículo derecho en la HAP. Por lo tanto, este péptido podría ser útil como blanco terapéutico en la HAP.
ABSTRACTS: Classic renin-angiotensis pathway (RAP) is activated in patients with pulmonary artery hypertension (PAH). We have previously shown that in patients with post myocardial infarction systolic dysfunction the activation of RAP mediated by angiotensin converting enzyme (ACE) and angiotensin II (Ang II) is inversely correlated with the parallel RAP axis mediated by homologous ACE (ACE2) and by the vasoactive and cardioprotective peptide Ang-(1-9). Pre clinical studies show that administration of Ang-(1-9) leads to a favorable ventricular remodelling. At present there is no information regarding levels of Ang-(1-9) in PAH patients compared to healthy subjects. Methods: 16 PAH patients (WHO group 1), with mean PA pressure > 25mmHg being treated with furosemide (40%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) were compared with healthy subjects (n=14). mPAP, pro BNP, pulmonary vascular resistance (Wu), pulmonary capillary pressure (PCP mmHg), cardiac output (L/min), functional capacity (6 min walking test) (6mWT), and changes in right ventricular fractional area (RV FA), were measured in all subjects. Results: In HAP subjects, the eiotology of PAH was unknown in 87%, or HIV (13%). Functional class was I (6.2 %), II (68.3%) or III (25%). Mean PAP was 51.3±1.9. Compared to healthy subjects, PAH patients had significantly lower RV FA, ACE2 and Ang-(19) levels. Also they had greater ACE plasma activity and AngII circulating levels. Significant correlations were found between Ang-(1-9) and mPAP (-0.701, p < 0,001) and between Ang-(1-9) and RV FA (r = 0.549, p < 0,01). Conclusion: group I PAH subjects, circulating levels of Ang-(1-9) are significantly lower than in healthy subjects and are inversely related to PAP, severity of ventricular remodeling and right ventricular dysfunction. The use of Ang-(1-9) as a vasodilator and cardioprotector agent could be clinically useful in PAH subjects.
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Angiotensinas/sangre , Hipertensión Arterial Pulmonar/sangre , Péptidos , Estudios TransversalesRESUMEN
BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a homologue of angiotensin-converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1-9 and 1-7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. HYPOTHESIS: Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. ANIMALS: Forty-nine dogs with and 34 dogs without heart disease. METHODS: Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. RESULTS: Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1-12.1) as compared to control (2.2 mU/mg; IQR, 1.8-3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1-7, in dogs with CHF (486.7 pg/mL; IQR, 214.2-1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4-45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1-25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1-9 (preincubation, 10.3 pg/mL; IQR, 4.4-37.2; postincubation, 2431 pg/mL; IQR, 1355-3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6-226.4; postincubation, 2.4 pg/mL; IQR, 0.50-5.8; P = .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.
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Angiotensinas/sangre , Cardiopatías/veterinaria , Peptidil-Dipeptidasa A/sangre , Enzima Convertidora de Angiotensina 2 , Animales , Estudios de Casos y Controles , Perros , Femenino , Cardiopatías/sangre , Cardiopatías/enzimología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/veterinaria , Inmunohistoquímica , Riñón/enzimología , Masculino , Miocardio/enzimología , Péptidos/sangre , Peptidil-Dipeptidasa A/análisis , Sistema Renina-AngiotensinaRESUMEN
BACKGROUND: In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity. METHODS: Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case-control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry. RESULTS: In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients. CONCLUSIONS: AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.
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Enfermedad de Addison/fisiopatología , Aldosterona/fisiología , Sistema Renina-Angiotensina/fisiología , Enfermedad de Addison/complicaciones , Hormona Adrenocorticotrópica/sangre , Adulto , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Angiotensinas/sangre , Presión Sanguínea , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Renina/sangre , Factores de RiesgoRESUMEN
The renin-angiotensin system is a highly complex enzymatic system consisting of multiple peptide hormones, enzymes, and receptors. Here, an assay to simultaneously quantify eight angiotensin peptides and bradykinin in human serum was developed and validated, using ultra high performance liquid chromatography coupled with tandem mass spectrometry. A pre-concentration method of Sephadex LH-20 gel solid-phase extraction was first applied for analysis of angiotensin peptides from serum sample. The triple quadrupole mass spectrometer was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The analytical time was within 5 min, much raising the analysis efficiency. Limits of detection ranged from 0.9 to 1.3 pg/mL, and displayed the same level of sensitivity compared with radioimmunoassay. The method was successfully applied to 22 healthy human serum samples, giving the concentrations of angiotensin I, angiotensin II, angiotensin III, angiotensin IV, angiotensin 1-9, angiotensin 1-7, angiotensin 1-5, Asn1 ,Val5 -Angiotensin II, and bradykinin for reference. This novel metabolic profile study of vasoactive peptides based on gel solid-phase extraction concentration provided not only an accurate quantitative assay of the serum concentrations, but also a promising methodology for evaluating the diagnostic values of the various peptides.
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Angiotensinas/sangre , Dextranos/química , Extracción en Fase Sólida , Adulto , Cromatografía Líquida de Alta Presión , Geles/química , Humanos , Persona de Mediana Edad , Espectrometría de Masas en TándemRESUMEN
Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a shortage of data regarding ivabradine's interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine is able to protect a hypertensive heart in the model of L-NAME-induced hypertension and to interfere with the RAAS. Four groups (n = 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day), L-NAME (40 mg/kg/day), and L-NAME plus ivabradine. L-NAME administration increased systolic blood pressure (SBP) and left ventricular (LV) weight, enhanced hydroxyproline concentration in the LV, and deteriorated the systolic and diastolic LV function. Ivabradine reduced heart rate (HR) and SBP, and improved the LV function. The serum concentrations of angiotensin Ang 1â»8 (Ang II), Ang 1â»5, Ang 1â»7, Ang 1â»10, Ang 2â»8, and Ang 3â»8 were decreased in the L-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by L-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in L-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level.
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Fármacos Cardiovasculares/farmacología , Hipertensión/etiología , Hipertensión/fisiopatología , Ivabradina/farmacología , NG-Nitroarginina Metil Éster/efectos adversos , Sistema Renina-Angiotensina/efectos de los fármacos , Aldosterona/sangre , Angiotensinas/sangre , Animales , Biomarcadores , Presión Sanguínea/efectos de los fármacos , Colágeno/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Hidroxiprolina/sangre , Hidroxiprolina/metabolismo , Hipertensión/diagnóstico , Hipertensión/metabolismo , Masculino , Ratas , Renina/sangre , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1-8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (≥30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1-8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake.
Asunto(s)
Alostasis , Presión Sanguínea , Dieta , Sistema Renina-Angiotensina/fisiología , Aldosterona/sangre , Angiotensinógeno/sangre , Angiotensinas/sangre , Angiotensinas/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Losartán/farmacología , Venas Mesentéricas/metabolismo , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/metabolismo , Fenilefrina/farmacología , Ratas , Ratas Endogámicas F344 , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Renina/sangre , Renina/metabolismoRESUMEN
OBJECTIVES: Preterm birth appears to contribute to early development of cardiovascular disease, but the mechanisms are unknown. Prematurity may result in programming events that alter the renin-angiotensin system. We hypothesized that prematurity is associated with lower angiotensin-(1-7) in adolescence and that sex and obesity modify this relationship. METHODS: We quantified angiotensin II and angiotensin-(1-7) in the plasma and urine of 175 adolescents born preterm and 51 term-born controls. We used generalized linear models to estimate the association between prematurity and the peptides, controlling for confounding factors and stratifying by sex and overweight/obesity. RESULTS: Prematurity was associated with lower plasma angiotensin II (ß: -5.2âpmol/l, 95% CI: -10.3 to -0.04) and angiotensin-(1-7) (-5.2âpmol/l, 95% CI: -8.4 to -2.0) but overall higher angiotensin II:angiotensin-(1-7) (3.0, 95% CI: 0.9-5.0). The preterm-term difference in plasma angiotensin-(1-7) was greater in women (-6.9âpmol/l, 95% CI: -10.7 to -3.1) and individuals with overweight/obesity (-8.0âpmol/l, 95% CI: -12.2 to -3.8). The preterm-term difference in angiotensin II:angiotensin-(1-7) was greater among those with overweight/obesity (4.4, 95% CI: 0.6-8.1). On multivariate analysis, prematurity was associated with lower urinary angiotensin II:angiotensin-(1-7) (-0.13, 95% CI: -0.26 to -0.003), especially among the overweight/obesity group (-0.38, 95% CI: -0.72 to -0.04). CONCLUSION: Circulating angiotensin-(1-7) was diminished whereas urinary angiotensin-(1-7) was increased relative to angiotensin II in adolescents born preterm, suggesting prematurity may increase the risk of cardiovascular disease by altering the renin-angiotensin system. Perinatal renin-angiotensin system programming was more pronounced in women and individuals with overweight/obesity, thus potentially augmenting their risk of developing early cardiovascular disease.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Recien Nacido Prematuro , Obesidad Infantil , Adolescente , Angiotensinas/sangre , Angiotensinas/orina , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/orina , Estudios de Casos y Controles , Femenino , Humanos , Masculino , North Carolina/epidemiología , Embarazo , Sistema Renina-Angiotensina , Factores SexualesRESUMEN
BACKGROUND: Angiogenin (ANG) is a multifunctional angiogenic protein that participates in both normal development and diseases. Abnormal serum ANG levels are commonly reported in various diseases. However, whether ANG can serve as a diagnostic or prognostic marker for different diseases remains a matter of debate. METHODS: Here, we performed a systematic review and meta-analysis of the literature utilizing PubMed, Web of Science, and Scopus search engines to identify all publications comparing plasma or serum ANG levels between patients with different diseases and healthy controls, as were studies evaluating circulating ANG levels in healthy populations, pregnant women, or other demographic populations. RESULTS: This study demonstrated that the serum ANG concentration in healthy populations was 336.14 ± 142.83 ng/ml and remained relatively stable in different populations and regions. We noted no significant differences in serum ANG levels between patients and healthy controls, except in cases in which patients suffered from cancer or cardiovascular diseases. The serum ANG concentrations were significantly higher in patients who developed colorectal cancer, acute myeloid leukemia, multiple myeloma, myelodysplastic syndromes, and heart failure than those in healthy controls. CONCLUSION: ANG has the potential of being a serum biomarker for cancers and cardiovascular diseases.
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Angiotensinas/sangre , Neoplasias Colorrectales/sangre , Insuficiencia Cardíaca/sangre , Leucemia Mieloide/sangre , Mieloma Múltiple/sangre , Síndromes Mielodisplásicos/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , MasculinoRESUMEN
AIM: To evaluate the role of adenovirus-mediated transduction human VEGF isoform 165 via direct myocardial injection in rats with an occluded circumflex coronary artery, and the possible underlying mechanism. METHODS: Sprague-Dawley rats were induced myocardial infarction (MI) with ligation of the left coronary artery. Rats were randomly divided into 4 groups: 1) the sham group; 2) the MI group; 3) the NS (normal saline) group and 4) the VEGF group. Direct myocardial injection of 0.1 ml rAAV-hVEGF165 (virus titer, 2×1010 v.p./ml) was performed in the border zone of myocardial infarction in the VEGF group at 3 different sites, whereas 0.1 ml of normal saline was injected in the NS group. 4 weeks after treatment, the serum levels of atrial natriuretic peptide (ANP), angiotensin-II (Ang II), tumor necrosis factor-α (TNF-α), and endothelin-1 (ET-1) were detected by competitive radioimmunoassay. The level of VEGF, Bax, and Bcl-2 was assessed by IHC. RESULTS: The whole heart weight, left heart weight, heart mass index and left heart mass index in the VEGF group were higher than those in the MI and NS group. VEGF treatment could also significantly increase cardiac function, and increase microvessel density in the infarcted area. Moreover, VEGF treatment could decrease the serum neurohumoral factors (ANP, Ag II, and TE-1), and inhibit myocardial apoptosis via TNF-α, Bax, and Bcl-2. CONCLUSION: Adenovirus-mediated VEGF165 gene therapy could significantly improve cardiac function possibly by inducing myocardial collateral vessel development, inhibiting the apoptosis of myocardial cells, and inhibiting ventricular remodeling.
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Adenoviridae , Terapia Genética/métodos , Infarto del Miocardio/terapia , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Adenoviridae/genética , Adenoviridae/metabolismo , Análisis de Varianza , Angiotensinas/sangre , Animales , Factor Natriurético Atrial/sangre , Factor Natriurético Atrial/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Endotelina-1/sangre , Masculino , Infarto del Miocardio/diagnóstico por imagen , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Ultrasonografía Doppler en Color , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Chronic liver diseases with portal hypertension are characterized by a progressive vasodilatation, endothelial dysfunction, and NADPH oxidase-derived vascular oxidative stress, which have been suggested to involve the angiotensin system. This study evaluated the possibility that oral intake of polyphenol-rich blackcurrant juice (PRBJ), a rich natural source of antioxidants, prevents endothelial dysfunction in a rat model of cirrhosis induced by chronic bile duct ligation (CBDL), and, if so, determined the underlying mechanism. Male Wistar rats received either control drinking water or water containing 60 mg/kg gallic acid equivalents of PRBJ for 3 weeks before undergoing surgery with CBDL or sham surgery. After 4 weeks, vascular reactivity was assessed in mesenteric artery rings using organ chambers. Both the acetylcholine-induced nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations in mesenteric artery rings were significantly reduced in CBDL rats compared to sham rats. An increased level of oxidative stress and expression of NADPH oxidase subunits, COX-2, NOS, and of the vascular angiotensin system are observed in arterial sections in the CBDL group. Chronic intake of PRBJ prevented the CBDL-induced impaired EDH-mediated relaxation, oxidative stress, and expression of the different target proteins in the arterial wall. In addition, PRBJ prevented the CBDL-induced increase in the plasma level of proinflammatory cytokines (interleukin [IL]-1α, monocyte chemotactic protein 1, and tumor necrosis factor α) and the decrease of the anti-inflammatory cytokine, IL-4. Altogether, these observations indicate that regular ingestion of PRBJ prevents the CBDL-induced endothelial dysfunction in the mesenteric artery most likely by normalizing the level of vascular oxidative stress and the angiotensin system.
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Endotelio Vascular/efectos de los fármacos , Hipertensión Portal/fisiopatología , Cirrosis Hepática/fisiopatología , Arterias Mesentéricas/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Ribes/química , Angiotensinas/sangre , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ciclooxigenasa 2/sangre , Citocinas/sangre , Endotelio Vascular/fisiopatología , Jugos de Frutas y Vegetales , Hipertensión Portal/sangre , Hipertensión Portal/tratamiento farmacológico , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/sangre , Cirrosis Hepática/tratamiento farmacológico , Masculino , Arterias Mesentéricas/fisiopatología , NADPH Oxidasas/sangre , Óxido Nítrico/sangre , Óxido Nítrico Sintasa de Tipo III/sangre , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Extractos Vegetales/uso terapéutico , Polifenoles/uso terapéutico , Ratas Wistar , Especies Reactivas de Oxígeno/sangre , Vasodilatación/efectos de los fármacosRESUMEN
Cytosolic NADH-cytochrome-b5-oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues. We have previously reported that global ablation of NCB5OR in mice results in early-onset lean diabetes with decreased serum leptin levels and increased metabolic and feeding activities. The conditional deletion of NCB5OR in the mouse cerebellum and midbrain (conditional knock out, CKO mice) results in local iron dyshomeostasis and altered locomotor activity. It has been established that lesion to or removal of the cerebellum leads to changes in nutrient organization, visceral response, feeding behavior, and body weight. This study assessed whether loss of NCB5OR in the cerebellum and midbrain altered feeding or metabolic activity and had an effect on serum T3, cortisol, prolactin, and leptin levels. Metabolic cage data revealed that 16 week old male CKO mice had elevated respiratory quotients and decreased respiratory water expulsion, decreased voluntary exercise, and altered feeding and drinking behavior compared to wild-type littermate controls. Most notably, male CKO mice displayed higher consumption of food during refeeding after a 48-h fast. Echo MRI revealed normal body composition but decreased total water content and hydration ratios in CKO mice. Increased serum osmolality measurements confirmed the dehydration status of male CKO mice. Serum leptin levels were significantly elevated in male CKO mice while prolactin, T3, and cortisol levels remain unchanged relative to wild-type controls, consistent with elevated transcript levels for leptin receptors (short form) in the male CKO mouse cerebellum. Taken together, these findings suggest altered feeding response post starvation as a result of NCB5OR deficiency in the cerebellum.