Armando el Rompecabezas Fisiopatológico del COVID-19 / Assembling the Physiopathology Puzzle of COVID-19

Un nuevo coronavirus hace su aparición en China a fines del año 2019, produciendo infección respiratoria aguda y falla respiratoria. Debido a su similitud clínica y microbiológica con el agente del síndrome respiratorio agudo grave (SARS por sus siglas en inglés), el SARS-CoV1, que afecto a China en el año 2003, fue bautizado como SARS-CoV2, y la enfermedad que produce como COVID-19 (COronaVIrus Disease 2019). Desde su identificación el mundo médico se vio inundado de reportes estadísticos, tablas y cifras que hacen al comportamiento epidemiológico del SARSCoV2, pero pocos autores han focalizado su investigación en los mecanismos patogénicos y si lo han hecho sus artículos han sido diluidos por la vorágine de datos estadísticos. El objetivo del presente trabajo es profundizar en los aspectos fisiopatológicos de la infección por SARS-CoV2 para lo cual realicé una revisión de la literatura desde el inicio de la actual pandemia hasta el mes de junio de 2020, utilizando para la búsqueda Mendeley y PubMed, centrado sobre todo en la capacidad del virus de alterar el delicado balance entre la angiotensina II y sus antagonistas, analizar las posibles razones de la peor evolución en un subgrupo de pacientes y proponer medidas terapéuticas enfocadas en estos hallazgos. El SARS-CoV2 infecta células que expresan el receptor primario para el virus, la enzima ACE2, presente en epitelio intestinal y respiratorio, así como en endotelio. Genera inicialmente hipoxia por lesión alveolar para luego generar disfunción endotelial por lesión directa, lesión mediada por anticuerpos, tormenta de citoquinas y alteración del balance entre la angiotensina II y sus antagonistas funcionales, con eventual trombosis en territorio pulmonar y sistémico, así como hemólisis angiopática y por hiperactividad macrofágica. La retroalimentación positiva entre hipoxia, inflamación y angiotensina II potencian el desarrollo de un síndrome de distrés y fallo multiorgánico, con escalada de la mortalidad. El análisis de la fisiopatología probable en la infección por SARS-CoV2 permite sacar algunas conclusiones siendo las centrales que el endotelio es uno de los actores centrales en la patogenia de la enfermedad y que los pacientes con mayor riesgo de complicaciones son aquellos con disfunción endotelial previa debida a la presencia de obesidad, diabetes mellitus o hipertensión, así como que existen diferentes fases o estadios, cada uno con una posible intervención terapéutica particular, es decir, que la COVID-19 es diferente entre pacientes y en el mismo paciente es diferente en el tiempo, con cada momento requiriendo una intervención terapéutica particular.

A new coronavirus makes its appearance in China in late 2019, causing acute respiratory infection and respiratory failure. Due to its clinical and microbiological similarity to the agent of severe acute respiratory syndrome (SARS), SARS-CoV1, which affected China in 2003, was named SARS-CoV2, and the disease it produces as COVID-19 (COronaVIrus Disease 2019). Since its identification, the medical world has been flooded with statistical reports, tables and figures regarding the epidemiological behavior of SARS-CoV2, but few authors have focused their research on pathogenic mechanisms and if they have, their articles have been diluted by the maelstrom of statistical data. The objective of the present work is to delve into the pathophysiological aspects of SARS-CoV2 infection, for which I carried out a literature review from the start of the current pandemic until June 2020, using Mendeley and PubMed for the search, focused above all on the ability of the virus to alter the delicate balance between angiotensin II and its antagonists, to analyze the possible reasons for the worse evolution in a subgroup of patients and to propose therapeutic measures focused on these findings. SARS-CoV2 infects cells that express the primary receptor for the virus, the enzyme ACE2, present in the intestinal and respiratory epithelium, as well as the endothelium. Initially, it generates hypoxia due to alveolar injury and then generates endothelial dysfunction due to direct injury, antibody-mediated injury, cytokine storm and alteration of the balance between angiotensin II and its functional antagonists, with eventual thrombosis in pulmonary and systemic territory, as well as angiopathic hemolysis and due to macrophage hyperactivity. The positive feedback between hypoxia, inflammation and angiotensin II potentiates the development of a distress syndrome and multi-organ failure, with an increase in mortality. The analysis of the probable pathophysiology in SARS-CoV2 infection allows us to draw some conclusions, the main ones being that the endothelium is one of the central actors in the pathogenesis of the disease and that the patients with the highest risk of complications are those with previous endothelial dysfunction, due to the presence of obesity, diabetes mellitus or hypertension, as well as that there are different phases or stages, each with a possible particular therapeutic intervention, that is, that COVID-19 is different between patients and in the same patient it is different in time, with each moment requiring a particular therapeutic intervention.

Lo mejor del Congreso 2019 de la Sociedad Europea de Cardiología / The best of the 2019 European Society of Cardiology Congress / O melhor do Congresso da Sociedade Europeia de Cardiologia 2019

Resumen: El Congreso Europeo de Cardiología constituye uno de los eventos más relevantes de la comunidad cardiológica mundial. Fue realizado entre el 31 de agosto y el 4 de setiembre en el corazón de París, siendo el tema central la salud cardiovascular global. Como es habitual, contó con la presencia de más de 30.000 profesionales y destacados invitados. Se presentaron actualizaciones de varias guías de práctica clínica e importantes trabajos científicos que sin duda impactarán en el tratamiento de los pacientes con patología cardiovascular. A continuación realizaremos un breve resumen de algunos de los trabajos presentados: - A trial to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and reduced left ventricular ejection fraction: DAPA-HF - Complete revascularization with multivessel PCI for myocardial infarction: the COMPLETE Trial - Angiotensin-neprylysin inhibition in heart failure with preserved ejection fraction: the PARAGON-HF - Antithrombotic therapy for atrial fibrillation with stable coronary disease: the AFIRE Investigators - Ticagrelor or prasugrel in patients with acute coronary syndromes: the ISAR-REACT 5 Trial

Summary: The European Congress of Cardiology is one of the most relevant events of the world cardiology community. It was held from August 31 to September 4 in the heart of Paris, France, the central theme being global cardiovascular health. As usual, it was attended by more than 30,000 professionals and prominent guests. Updates of several clinical practice guides and important scientific papers were presented. These undoubtedly will impact in the treatment of patients with cardiovascular pathology. Below we present a brief summary of some of the trials presented: - A trial to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and reduced left ventricular ejection fraction: DAPA-HF - Complete revascularization with multivessel PCI for myocardial infarction: the COMPLETE Trial - Angiotensin-neprylysin inhibition in heart failure with preserved ejection fraction: the PARAGON-HF - Antithrombotic therapy for atrial fibrillation with stable coronary disease: the AFIRE Investigators - Ticagrelor or prasugrel in patients with acute coronary syndromes: the ISAR-REACT 5 Trial

Sumário: O Congresso Europeu de Cardiologia é um dos eventos mais relevantes da comunidade mundial de cardiologia. Foi realizada de 31 de agosto ao 4 de setembro no coração de Paris, na França, o tema central foi a saúde cardiovascular global. Como sempre, participaram mais de 30.000 profissionais e convidados de destaque. Atualizações de vários guias de prática clínica e importantes artigos científicos foram apresentados que, sem dúvida, impactarão o tratamento de pacientes com patologia cardiovascular. Abaixo, faremos um breve resumo de alguns trials apresentados: - A trial to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and reduced left ventricular ejection fraction: DAPA-HF - Complete revascularization with multivessel PCI for myocardial infarction: the COMPLETE Trial - Angiotensin-neprylysin inhibition in heart failure with preserved ejection fraction: the PARAGON-HF - Antithrombotic therapy for atrial fibrillation with stable coronary disease: the AFIRE Investigators - Ticagrelor or prasugrel in patients with acute coronary syndromes: the ISAR-REACT 5 Trial

Influence of ACE polymorphism on echocardiographic data of patients with heart failure / Influência do polimorfismo da ECA nos dados ecocardiográficos de pacientes com insuficiência cardíaca

Background: Angiotensin converting enzyme (ACE) polymorphism has been associated with different clinical and echocardiographic parameters in patients with heart failure (HF). However, no studies have been investigated such association with HF caused by Chagas disease. Objectives: To perform a genetic study to evaluate the frequency of ACE polymorphism in patients with HF caused by Chagas disease attending a university hospital in the central-west region and its association with echocardiographic findings. Methods: Descriptive study of ACE polymorphism (I/D) and echocardiographic data of 103 patients with HF caused by Chagas disease. Echocardiographic parameters were compared between the genotypes using the ANOVA test. Results: Genotypic distribution of the ACE polymorphism was 16.5% DD, 57.3% DI and 26.2% II. There was no statistically significant difference in the distribution of genotypes between men and women. The echocardiographic findings were: left ventricular ejection fraction: 43.8 ± 14.8 (DD) vs. 42.3 ± 11.6 (ID) vs. 44.9 ± 13.0 (II), p = 0.664; left ventricular diastolic diameter: 59.2 ± 9.7 (DD) vs. 60.3 ± 7.6 (ID) vs. 59.7 ± 78.1 (II), p = 0.879; left ventricular systolic diameter: 48.6 ± 12.8 (DD) vs. 50.6 ± 9.7 (ID) vs. 49.3 ± 11.9 (II), p = 0.753; and left atrial volume: 44.9 ± 10.1 (DD) vs. 40.9 ± 9.6 (ID) vs. 38.2 ± 7.8 (II), p = 0.068. Significant correlation coefficients were found for gender, age, ethnicity, heart rate and dyslipidemia. Conclusion: ACE polymorphism was not associated with echocardiographic findings in patients with HF caused by Chagas disease

Correlation of the levels of angiotensin II and angiotensin (1-7) with the degree of chronic hepatitis B liver fibrosis / 临床肝胆病杂志

@#ObjectiveTo investigate the differences in the plasma levels of angiotensin II (Ang II) and angiotensin (1-7) ［Ang(1-7)］ in different stages among patients with chronic hepatitis B (CHB) liver fibrosis and their significance in the pathogenesis of liver fibrosis. MethodsA prospective study was performed. A total of 86 patients with hepatitis B virus (HBV) infection who attended our hospital from March 2017 to March 2019 were enrolled and divided into CHB group (group A) with 25 patients, compensated hepatitis B cirrhosis group (group B) with 31 patients, and decompensated hepatitis B cirrhosis group (group C) with 30 patients. The double-antibody sandwich method was used to measure the plasma levels of Ang II and Ang(1-7), and FibroTouch scan was used for liver stiffness measurement (LSM). A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between groups. A binary linear correlation analysis was used to investigate the correlation of the plasma levels of Ang II and Ang(1-7) with LSM; a Spearman rank correlation analysis was used to investigate the correlation of the plasma levels of Ang II and Ang(1-7) with the progression of CHB liver fibrosis; a logistic regression analysis was used to evaluate the value of Ang II, Ang(1-7), and LSM in predicting hepatitis B cirrhosis. ResultsWith the progression of liver fibrosis from group A to group C, there was a significant increase in course of disease (5.2±1.3 years vs 7.8±1.6 years vs 10.1±1.5 years, F=4.266, P=0.002), a significant reduction in the proportion of patients receiving antiviral therapy (76.00% vs 64.52% vs 53.33%, χ２=5.544, P＜0.001), significant increases in Ang II (51.01±868 pg/ml vs 74.38±10.05 pg/ml vs 102.78±13.22 pg/ml, F=520.260, P<0.001), Ang II/Ang(1-7) ratio (1.06±0.41 vs 232±023 vs 5.82±1.24, F=18.860, P＜0.001), and LSM (6.85±1.26 kPa vs 18.25±3.22 kPa vs 26.84±7.57 kPa, F=93.260, P＜0001), and a significant reduction in Ang(1-7) (45.93±10.24 pg/ml vs 31.52±9.62 pg/ml vs 16.55±9.48 pg/ml, F=209.860, P＜0001). Ang II and Ang II/Ang(1-7) ratio were positively correlated with LSM (r=0.623 and 0.813, both P＜0.01), while Ang(1-7) was negatively correlated with LSM (r=-0.677, P＜0.01). Ang II, Ang II/Ang(1-7) ratio, and LSM gradually increased with the progression of liver fibrosis (r=0639, 0.886, and 0.712, all P＜0.01), while Ang(1-7) was negatively correlated with the progression of liver fibrosis (r=-0.653, P＜0.01). Ang II/Ang(1-7) ratio and LSM had an early warning effect for liver cirrhosis in patients with HBV infection (odds ratio=1884 and 2.015, both P＜0.01). ConclusionIn patients with HBV infection, there are gradual increases in Ang II and Ang II/Ang(1-7) ratio and a gradual reduction in Ang(1-7) with the aggravation of liver fibrosis. Dynamic monitoring of the plasma levels of Ang II and Ang(1-7) can provide a reference for real-time assessment of liver fibrosis and decision-making in clinical diagnosis and treatment.

Effect of agonist of angiotensin-(1-7) on atherogenesis in apolipoprotein E-knockout mice / 中华老年医学杂志

Objective To investigate the effects of agonist of angiotensin-(1-7)(AVE0991) on endothelial function and atherogenesis in apolipoprotein E knockout (ApoE-/-) mice.Methods Eight-week-old ApoE-/-male mice and C57BL/6J male mice were randomly divided into 3 groups:a normal diet control group(ND,n=10),a high-fat diet group(HFD,n=10),and a high-fat diet with AVE0991 0.58 μmol · kg-1 · d-1 group(HFD+ AVE0991,n=10).After 12 weeks of treatment,serum levels of lipids and parameters of endothelial function were measured.Atherosclerotic lesions in aorta roots were detected by Oil Red O staining.CD31 levels in the arterial intima were analyzed by immunohistochemistry.Results AVE0991 had no effects on blood lipids (P ＞ 0.05)but lowered serum levels of nitric oxide in high-fat diet mice(76.8±34.4 μmol/L vs.116.8±33.9 μmol/L,P＜0.05).Also,AVE0991 had no effects on the activity of serum nitric oxide synthase(19.5±5.7 U/ml vs.17.9±3.3 U/ml,P＞0.05)but decreased the activity of serum induced nitric oxide synthase(9.0 ±2.3 U/ml vs.12.7 ± 3.2 U/ml,P ＜0.05) and increased the ratio of phosphorylated endothelial nitric oxide synthase to induced nitric oxide synthase in the vessel wall in high-fat diet mice(0.8±0.2％ vs.0.6 ± 0.2％,P ＜ 0.05).AVE0991 decreased serum levels of C-reactive protein,tumor necrosis factor-α and interleukin-6 (P ＜ 0.05),and decreased the area percentage of atherosclerotic lesions in aorta roots (15.6 ± 3.3 ％ vs.45.4 ± 9.8 ％,P ＜ 0.05) and increased the integrated optical density of CD31 in the arterial intima in high-fat diet mice(54.1±11.0％ vs.28.7±10.6％,P＜0.05)Conclusions AVE0991 can attenuate atherogenesis in ApoE-/-mice fed a high-fat diet,possibly via reducing inflammatory response,regulating the activity of nitric oxide synthases and improving endothelial functions.

Fisiopatología de la hipertensión arterial: nuevos conceptos

La fisiopatología de la hipertensión arterial es compleja, pues intervienen múltiples factores que, en su mayoría, tienen una base genética. Se ha podido mostrar que es el sistema renina-angiotensina-aldosterona (SRAA) el que tiene mayor importancia, puesto que condiciona la acción de otros factores humorales y/o neurales, tales como producción de endotelina, la inhibición del óxido nítrico o de la prostaciclina, la acción de catecolaminas o de vasopresina, del factor ouabaína-sensible o FDE, del tromboxano A2 (TxA2) y de diversas sustancias vasopresoras endógenas. Se presenta en este artículo una revisión exhaustiva de lo que conocemos hoy acerca del SRAA. Y se incluye algunas novedades de la investigación del SRAA.

The pathophysiology of hypertension is complex because it involves multiple factors which mostly have a genetic basis. It has been shown that the renin-angiotensinaldosterone system (RAAS) is the most important factor, since it determines the action of other humoral and/or neural factors such as production of endothelin, inhibition of nitric oxide or prostacyclin, action of catecholamines, vasopressin, ouabain-sensitive factor, thromboxane A2 (TxA2) and various vasopressor endogenous agents. In this article, we present a thorough review of what we know today about the RAAS. We also include some new research on this system.

Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1–7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1–7)/Mas receptor and ACE2/Ang-(1–9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats / Perfil de citocinas urinárias de acordo com o local de bloqueio do sistema renina angiotensina em ratos nefrectomizados

Abstract Introduction: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS) impacts the levels of inflammation and fibrosis biomarkers. Objective: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD). Methods: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy), or subjected to sham surgery (control). Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg); ¾ Nephrectomy receiving candesartan (10 mg/kg) and ¾ Nephrectomy receiving aliskiren (10 mg/kg). Urine output, water intake, mean arterial pressure (MAP) and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL) -1β, IL-6, IL-10 and transforming growth factor beta (TGF-β) were measured. Results: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1β, while only candesartan reduced TGF-β and only aliskiren increased IL-10. Conclusion: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

Resumo Introdução: Ainda não se sabe como a inibição farmacológica do Sistema Renina Angiotensina (SRA) afeta os níveis de biomarcadores de inflamação e fibrose. Objetivo: Este estudo pretendeu avaliar o efeito de enalapril, candesartan e alisquireno sobre os níveis urinários de citocinas em um modelo de doença renal crônica (DRC). Métodos: Ratos Wistar machos foram submetidos à remoção cirúrgica de ¾ do parênquima renal para induzir DRC (nefrectomia), ou submetidos à cirurgia fictícia (controle). Animais foram então randomizados em cinco grupos: Cirurgia fictícia recebendo veículo; Nefrectomia recebendo veículo; Nefrectomia recebendo enalapril (10 mg/kg); Nefrectomia recebendo candesartan (10 mg/kg) e Nefrectomia recebendo alisquireno (10 mg/kg). Débito urinário, ingesta hídrica, pressão arterial media (PAM) e concentrações urinárias de creatinina, ureia, albumina, Na+, K+, interleucina (IL) -1β, IL-6, IL-10 e fator de transformação e crescimento beta (TGF-β) foram medidas. Resultados: A nefrectomia comprometeu significativamente a função renal, aumentou a PAM e alterou os níveis de todas as citocinas avaliadas na urina. Enalapril, candesartan e alisquireno melhoraram a função renal e diminuíram a PAM e a IL-6 quando comparado aos grupo de animais nefrectomizados tratados com veículo. Candesartan e alisquireno reduziram IL-1β, enquanto somente candesartan diminuiu o TGF-β e somente alisquireno aumentou a IL-10. Conclusão: Enalapril, candesartan e alisquireno apresentaram efeitos similares em relação à melhora da função renal e redução da PAM e dos níveis urinários de IL-6 em ratos com DRC. Por outro lado, o perfil de citocinas diferiu de acordo com o tratamento, sugerindo que diferentes mecanismos sejam desencadeados em resposta ao local de bloqueio do SRA.

Effects and related mechanism of angiotensin-(1-7) on Toll-like receptor 4-mediated oxidative stress in human umbilical vein endothelial cells / 中华心血管病杂志

Objective@#To explore the role and related mechanisms of angiotensin-(1-7)(Ang-(1-7)) on Toll-like receptor 4 (TLR4) mediated oxidized low-density lipoprotein(ox-LDL)-induced oxidative stress in human umbilical vein endothelial cells (HUVECs).@*Methods@#HUVECs were cultured in vitro and divided into six groups: the control group (normal medium), the ox-LDL group(treated with 75 mg/L ox-LDL), the ox-LDL+ Ang-(1-7) group (1 μmol/L Ang-(1-7) pretreated for 30 minutes, then intervened with 75 mg/L ox-LDL), the ox-LDL+ Ang-(1-7)+ A-779 group(1 μmol/L A-779 (Mas receptor) pretreated for 30 minutes, 1 μmol/L Ang-(1-7) pretreated for 30 minutes, then intervened with 75 mg/L ox-LDL), the ox-LDL+ A-779 group (1 μmol/L A-779 pretreated for 30 minutes, then intervened with 75 mg/L ox-LDL), the ox-LDL+ HTA125 group (10 μg/L HTA125 (TLR4-blocking antibody) pretreated for 30 minutes, then intervened with 75 mg/L ox-LDL ). The corresponding index was detected after 24 hours after intervention. Apoptosis of cells were detected by Annexin V-FITC/PI double staining flow cytometry and transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL). The generation of reactive oxygen species (ROS), products in oxidative stress, were detected by DCFH-DA staining. The mRNA and protein expression levels of NADPH oxidase 4(NOX4) and TLR4 were detected by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analysis respectively.@*Results@#(1) The results of Annexin V-FITC/PI double staining flow cytometry showed that the proportion of apoptotic cells was higher in ox-LDL group than in control group ((21.18±1.40)% vs. (1.59±0.26)%, P<0.01), lower in ox-LDL+ Ang-(1-7) group((7.42±1.07)%) and ox-LDL+ HTA125 group((9.19±1.01)%) than in ox-LDL group (both P<0.01), higher in ox-LDL+ Ang-(1-7)+ A-779 group ((19.91±1.30)%) and ox-LDL+ A-779 group((20.47±0.95)%) than in ox-LDL+ Ang-(1-7) group (both P<0.01). (2) The TUNEL results showed that the proportion of apoptotic cells was higher in ox-LDL group than in control group((10.83±0.77)% vs. (2.83±0.82)%, P<0.01), lower in ox-LDL+ Ang-(1-7) group ((3.66±0.54)%)and ox-LDL+ HTA125 group((4.97±0.60)%) than in ox-LDL group(both P<0.01), higher in ox-LDL+ Ang-(1-7)+ A-779 group((10.69±0.62)%) and ox-LDL+ A-779 group((11.43±0.42)%) than in ox-LDL+ Ang-(1-7) group (both P<0.01). (3) ROS level was higher in ox-LDL group than in control group(0.093±0.014 vs. 0.053±0.011, P<0.01), lower in ox-LDL+ Ang-(1-7) group (0.063±0.011, P<0.01)and ox-LDL+ HTA125 group(0.070±0.010, P<0.05)than in ox-LDL group, higher in ox-LDL+ Ang-(1-7)+ A-779 group(0.088±0.003) and ox-LDL+ A-779 group(0.095±0.005) than in ox-LDL+ Ang-(1-7) group (both P<0.01). (4) The mRNA expression level of NOX4 was higher in ox-LDL group than in control group(11.74±0.65 vs. 1.00±0.00, P<0.01), lower in ox-LDL+ Ang-(1-7) group (2.85±0.75)and ox-LDL+ HTA125 group(5.57±0.52) than in ox-LDL group(both P<0.01), higher in ox-LDL+ Ang-(1-7)+ A-779 group(10.51±0.54) and ox-LDL+ A-779 group (11.04±1.01) than in ox-LDL+ Ang-(1-7) group (both P<0.01), higher in ox-LDL group than in control group(27.60±1.86 vs. 1.00±0.00, P<0.01), lower in ox-LDL+ Ang-(1-7) group (8.00±1.03)and ox-LDL+ HTA125 group(14.83±0.97)than in ox-LDL group(both P<0.01), higher in ox-LDL+ Ang-(1-7)+ A-779 group(24.81±2.19) and ox-LDL+ A-779 group (26.64±0.65)than in ox-LDL+ Ang-(1-7) group (both P<0.01). (5)The protein expression level of NOX4 was higher in ox-LDL group than in control group (0.61±0.09 vs. 0.23±0.02, P<0.01), lower in ox-LDL+ Ang-(1-7) group(0.27±0.03) and ox-LDL+ HTA125 group(0.22±0.02) than in ox-LDL group(both P<0.01), higher in ox-LDL+ Ang-(1-7)+ A-779 group (0.58±0.06)and ox-LDL+ A-779 group(0.61±0.03) than in ox-LDL+ Ang-(1-7) group (both P<0.01). The protein expression level of TLR4 was higher in ox-LDL group than in control group(0.18±0.02 vs. 0.08±0.01, P<0.01), lower in ox-LDL+ Ang-(1-7) group(0.07±0.01) and ox-LDL+ HTA125 group(0.09±0.01) than in ox-LDL group(both P<0.01), higher in ox-LDL+ Ang-(1-7)+ A-779 group(0.18±0.02) and ox-LDL+ A-779 group(0.20±0.02) than in ox-LDL+ Ang-(1-7) group (both P<0.01).@*Conclusion@#TLR4 mediated the ox-LDL induced injury in HUVECs, and Ang-(1-7) could attenuate ox-LDL induced injury in HUVECs by modulating the specific Mas receptors.

Expression and significance of classical ACE-AngII-AT1 axis and new ACE2-Ang (1-7)-Mas axis of renin-angiotensin system in local pancreas / 临床肝胆病杂志

The renin-angiotensin system (RAS) is a classical circulating enzyme pathway that plays an important role in regulation of pancreatic function. In recent years, with deepening understanding of RAS, researchers found that RAS not only includes the classical ACE-Ang II-AT1 axis, but also includes the new ACE2-Ang (1-7)-Mas axis. Extensive studies have confirmed that the ACE2-Ang (1-7)-Mas axis can antagonize the effect of the ACE-Ang II-AT1 axis. This paper reviews the composition and function of both axes of the RAS in the local pancreas, and also presents the comparison between the two axes.

The influence of trimetazidine(TMZ) on the cardiac function and neurohormonal of heart failure model in rats / 中国基层医药

Objective To observe the effects of trimetazidine (TMZ) on the cardiac function and neurohormonal of heart failure model in rats.Methods Partially banding abdominal aortic artery to achieve congestive heart failure rats model.Interventricular septum thickness(IVST),left ventricular posterior wall thickness(LVPWT),left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter (LVESD),left ventricular ejection fraction(LVEF) and shortening fraction(FS) were measured by echocardiogram,Pathological changes of myocardial cells was observed,B-type natriuretic peptide (BNP)、C-type natriuretic peptide receptor (NPRC),atrial natriuretic peptide (ANP),myosin heavy chain (β-MHC) and angiotensinl (AT1) were measured by Real-Time PCR,superoxide dismutase (SOD) was measured by immunohistochemistry method.Results Trimetazidine treatment of the high-dose group and the model group compare IVST LVPWT,LVESD,LVEDD were (0.63 ± 0.05) mn,(0.73 ± 0.06) mm,(0.73 ±0.05)mm,(0.87 ±0.06)mm and (1.07 ±0.06)mm,(1.13 ±0.06) mm,(0.93 ±0.06)mm,(1.33 ±0.06) mm,was significantly reduced (P ＜ 0.05),LVEF,FS increased to (27.75 ± 1.83) ％,(11.44 ± 0.76) ％ and (11.78 ±0.56)％,(4.27 ± 0.22)％ (P ＜ 0.01),Myocardial cell structure were remarkably improved.The expression of BNP,ANP,NPRC,ATI,β-MHC were remarkably decreased.The expression of SOD was elevated.Conclusion TMZ treatment group can improve the secretion of neurohormonal of heart failure model in rats,and also obviously improve the cardiac contractility.

Effect of angiotensin 1-7 on renal tubulointerstitial fibrosis of diabetic rats / 中华肾脏病杂志

Objective To investigate the effects of angiotensin1-7 (Ang1-7) on renal tubulointerstitial fibrosis of diabetic rats.Methods Thirty-two male Wistar rats were randomly divided into four groups: normal control group,diabetic group,telmisartan group,Ang1-7-treated group.For 9 weeks after diabetes mellitus model established,24 h proteinuria,urine NAG/Cr,glucose,insulin,TG,TC,BUN,Scr,Na+ and K+ were assessed.Renal pathological changes were evaluated by PAS staining; Expression of TGF-β1,PPARγ and α-SMA mRNA was deteeted by real-time PCR; Protein levels of PPARγ,α-SMA and TGF-β1 were detected by Western blotting.Results (1)At the end of the ninth week,the blood pressure,proteinuria,renal weight/body weight in group DM were significantly higher than those in group NC (P＜0.05).(2)Renal interstitial fibrosis in group DM was obviously severe as compared to group NC (P＜0.05),but was improved in group TM and group T(P＜0.05).(3)TGF-β1 and α-SMA mRNA in group DM were significantly increased,and PPARγ mRNA was significantly decreased.Compared with group DM,TGF-β1 and α-SMA mRNA were significantly decreased,and PPARγ mRNA was significantly increased in group TM and group T,especially in group T.(4)TGF-β1 and α-SMA in group DM were significantly increased,and PPARγ decreased significantly.Compared with group DM,TGF-β1 and α-SMA decreased significantly,PPARγ increased significantly in group TM and group T,especially in group T.Conclusion Ang1-7 inhibits high glucose-induced α-SMA expression in vivo through up-regulating the PPAR expression and may inhibit renal tubulointerstitial fibrosis of diabetic rats.

Influence of angiotensin-(1-7) on inducible nitric oxide synthase expression after focal cerebral ischemia-reperfusion in rats / 中华神经科杂志

Objective To investigate influence of Ang-(1-7) on the inducible nitric oxide synthase (iNOS) activity and gene expression following focal cerebral ischemia/reperfusion in rats. Methods Cerebral ischemia/reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male Sprague-Dawley (SD) rats. Ang-(1-7) or artificial cerebrospinal fluid (aCSF) was continuous administrated by implanted Alzet osmotic minipumps into lateral cerebral ventricle after reperfusion. Experimental animals were divided into sham-operated group ( sham operation + aCSF), aCSF treatment group(MCAO+aCSF)and ang-(1-7)treatment groups(MCAO+Ang-(1-7))at low(1 pmol·0.5 μl-1·h-1),medium (100 pmol·0.5 μl-1·h-1)or hith(10 nmol·0.5 μl-1·h-1)dose levels.The activity of iNOS in ischemic tissues were measured by iNOS detection kits. Reverse transcription( RT)-PCR was used to determine messenger RNA (mRNA) of the iNOS in ischemic tissues. Results The cerebral ischemic lesion resulted in a significant increase of iNOS expression compared with sham operation group. The high-dose Ang-(1-7) markedly enhanced (iNOS) activity ( 160. 83 vs 116. 75 U/mg, F = 19. 22,P＜0.01; 151.87 vs 113.07 U/mg, F=63.52,P＜0. 01) and gene expression(0.43 vs 0.38, F=21.83,P ＜ 0. 01; 0. 40 vs 0. 35, F = 19.49, P ＜ 0. 01 ) compared with aCSF treatment group at 24 hours and 48hours after reperfusion, whereas medium and low-dose Ang-( 1-7 ) didn't stimulate iNOS activation.Conclusions The obtained results suggest that high-dose Ang-(1-7) upregulate iNOS expression following ischemic stroke.Moreover,overdose Ang-(1-7)(10 nmol·0.5 μl-1·h-1)may have Ang Ⅱ-like effects in iNOS expression increase.

Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

Construction and MRI of angiotensin Ⅱ transiently induced abdominal aortic dissection in ApoE-/-mouse model / 中国医学影像技术

Objective To establish abdominal aortic dissection model in ApoE-/-mice, and to evaluate the ability of 7.0T MR to detect the abdominal aortic artery aneurysms in ApoE-/-mice in vivo. Methods ApoE-/-mice aged 10 months were infused with angiotensin Ⅱ with 14 days Osmotic minipump after 10 weeks of high lipid diet. Two different doses of angiotensin Ⅱ were given to mice, i.e. 1000 ng/(kg·min) and 500 ng/(kg·min), respectively. The contrast group was infused with saline water. The abdominal aortic artery was observed in vivo with MR before and within 14 days infusion. At last, the pathological changes of the abdominal artery were compared with MRI findings. Results After 6 or 7 days higher dose of angiotensin Ⅱ infusion, aortic dissection was seen. MR T2WI showed crescent-shaped high signal in the vessel wall of one side，the pathological study identified the hematoma between media and adventitia. Abdominal aortic dissection aneurysms were also found in the mice 13 or 14 days after lower dose of angiotensin Ⅱ infusion, which were consistent with pathological studies. Besides, the signal of the vessel wall was significantly higher in both T2WI and PDWI sequences. There was excellent agreement between MR and histopathology. 〖WTHZ〗 Conclusion Abdominal aortic dissection aneurysms model can be successfully established with different doses (1000 ng/(kg·min) and 500 ng/(kg·min)) of angiotensin Ⅱ infusion into ApoE-/-mice fed with high lipid diet. High-resolution MR is able to visualize the abdominal aortic dissection aneurysm formation in vivo.

Effect of angiotensin-(1-7) on proliferation and secretion of cultured rat's glomerular mesangial cells induced by transforming growth factor-β1 / 中国医师杂志

Objective To explore the effect of angiotensin-(1-7) [Ang-(1-7)] on proliferation and secretion in cultured rat's glo-merular mesangial cells(GMC) induced by transforming growth factor-β1 (TGF-β1). Methods GMC in logarithmic growth phase were in-cubated, and then were divided into 4 groups: control, Ang-(1-7), TGF-β1,and TGF-β1 + Ang-(1-7) group. Cell numbers of rat's GMC were detected by WST-1. Laminin(LN) and collagenlV (ColⅣ) mRNA expressions in GMC were analyzed by RT-PCR. The secretion of LN and ColⅣ in culture medium of rat's GMC was measured by radioimmunoassay. Results Ang-(1-7) significantly inhibited basal and TGF-β1-induced proliferation of cultured glomerular mesangial cells. Ang-(1-7) significantly down-regulated LN and Col Ⅳ mRNA expressions in glomerular mesangial cells and also inhibited the secretion of LN and ColⅣ induced by TGF-β1(P <0. 05). Conclusions Ang-(1-7) can inhibit basal and TGF-β1-induced proliferation, and inhibit ECM secretion of cultured rats glomerular mesangial cells.

Polymorphism of the Angiotensin II Type 1 Receptor A1166C in Korean Hypertensive Adolescents

BACKGROUND AND OBJECTIVES: The renin-angiotensin system (RAS) is a major regulator of blood pressure. The angiotensin II receptor type 1 (AGTR 1) A1166C has been extensively studied in searching for their involvement in the development of hypertension. The aim of this study was to determine the association of the AGTR 1 A1166C marker with essential hypertension in Korean adolescents. SUBJECTS AND METHODS: Forty hypertensive adolescents were included in this study. The obesity index (OI) and body mass index (BMI) of the subjects were calculated. Blood pressure was measured at the resting state by oscillometric methods. The serum aldosterone, renin, insulin, angiotensin converting enzyme (ACE), homocysteine, vitamin B12 and folate levels were measured. The carotid intima-media thickness (IMT) and diameter and the brachial-ankle pulse wave velocity (baPWV) were evaluated by ultrasound. Polymerase chain reaction (PCR) was conducted to amplify the DNA of each of the study subjects to analyze the polymorphism of AGTR 1 A1166C. RESULTS: The genotypic frequency of AA was 87.5%, that for adenylate cyclase (AC) was 12.5% and no CC type was detected. The serum homocysteine level was higher in the subjects with the AC genotype than that in the subjects with the AA genotype (11.9+/-2.9 umol/L vs 17.1+/-4.2 umol/L, respectively). The carotid IMT of the subjects with the AA genotype was greater than that of the subjects with the AC genotype (5.0+/-0.1 mm vs 8.0+/-0.2 mm, respectively). CONCLUSION: In conclusion, the A1166C mutation group had a significantly greater carotid IMT and higher homocysteine levels than the group with the normal genotype of AGTR 1. The AC genotype of A1166C may be useful to predict the presence of early coronary artery disease in hypertensive adolescents. More investigation is necessary to clarify the relation between the A1166C gene and its involvement with coronary artery disease in hypertensive Korean adolescents.

Functional protection and long-term survival of renal allograft by the combination of ACE inhibitor and angiotensin receptor blocker / 中华泌尿外科杂志

Objective To evaluate the role of the combination of angiotensin receptor blocker (ARB)and angiotensin corwerting enzyme inhibitor(ACEI)in functional protection and long-term survival of renal allograft. Methods Thirty-two renal transplant recipients without diabetes mellitus,whose albuminuria concentration in 24-hours collection was more than 0.5 g/d or serum Cr concentration was higher than 177 mmol/L,were randomly divided into experimental group(n=23,male 9 and female 14 cases,mean age 40 years)and control group(n=9,male 5 and female 4 cases,mean age 35 years).Combination of ARB(Valsartan,80rag Qd)and ACEI(Benazapril,20 mg Bid)theraPy was given to each patient every day for 3 years in experimental group.The recipients in control group never received this administration.The serum Cr concentration,albuminuria in 24-hours collection and survival of renal allograft were compared between the 2 groups after 3 years. Results There was significant difference(P＜0.05) of serum Cr concentration between experimental group and control group(252.2±117.9 mmol/L VS 375.3±203.0 mmol/L),especially for chronic allograft nephropathy (CAN)patieats(282.4±147.3 mmol/L vs 528.7±107.8 mmol/L,P＜0.01).There was no difference (P＞0.05)in terms of the values of alburninuria(1.0±0.6 g/d vs 1.3±0.7 g/d)and survival of renal allograft(76 months VS 71 months)after 3 years between 2 groups.Comclusion The administration of ARB+ACEI could protect function of renal allograft with different pathological changes especially for CAN.

Angiotensin-(1-7) inhibit the expression of c-fos in angiotensin II-induced proliferative glomerular mesangial cells / 中国医师杂志

Objective To investigate the effect of angiotensin-(1-7) on the expression of cellular c-fos in angiotensin II -induced proliferative glomerular mesangial cells (GMC). Methods GMC were treated with angiotensin II and different dose of angiotensin-(1-7). GMC number were evaluated by crystal violet staining and the expression of c-foe were detected by western blot. Results Angiotensin-(1-7) inhibit angiotensin II -induced GMC proliferation as well as the expression c-foe in a concentration dependent manner. Conclusion c-fos is involved in the inhibiting effects of angiotensin-(1-7) on angiotensin II -induced GMC proliferation.