SARS-CoV-2 Spike Protein Enhances Carboxypeptidase Activity of Angiotensin-Converting Enzyme 2.

In this study, we investigated whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein may modify angiotensin-converting enzyme 2 (ACE2) activity in the plasma, heart, kidney, liver, lung, and six brain regions (amygdala, brain stem, cortex, hippocampus, hypothalamus, and striatum) of diabetic and hypertensive rats. We determine ACE2 activity in the plasma and lysates of heart, kidney, liver, lung, and six brain regions. MLN-4760 inhibits ACE2 activity in the plasma and all organs. On the other hand, soluble ACE2 (sACE2) activity increased in the plasma of diabetic rats, and there was no change in the plasma of hypertensive rats. ACE2 activity was augmented in the liver, brain stem, and striatum, while it decreased in the kidney, amygdala, cortex, and hippocampus of diabetic rats. ACE2 activity increased in the kidney, liver, and lung, while it decreased in the heart, amygdala, cortex, and hypothalamus of hypertensive rats. We measured the ACE2 content via enzyme-linked immunosorbent assay and found that ACE2 protein levels increased in the heart, while it decreased in the plasma, kidney, brain stem, cortex, hippocampus, hypothalamus, and striatum of diabetic rats. ACE2 protein levels decreased in the brain stem, cortex, hippocampus, and hypothalamus of hypertensive rats. Our data showed that the spike protein enhanced ACE2 activity in the liver and lungs of diabetic rats, as well as in the heart and three of the brain regions (cortex, hypothalamus, and striatum) of hypertensive rats.

Hipertensión arterial sistémica posterior a COVID-19 / Systemic arterial hypertension after COVID-19

Introducción: un nuevo tipo de coronavirus que se nombró SARSCoV-2, responsable de la enfermedad por COVID-19, tuvo esparcimiento rápido en el mundo, por alta transmisión que resultó en pandemia. Se registraron 2'397,216 casos confirmados, con 162,956 defunciones en el mundo, de acuerdo con la Organización Mundial de la Salud (OMS), en abril de 2020. Sin embargo, la hipertensión afecta a 40% de adultos, lo que significa que alrededor de 250 millones de personas padecen de presión alta. La OMS, de acuerdo con sus reportes, refiere que la hipertensión es el factor de riesgo número uno de muerte. Uno de cada cuatro mexicanos padece hipertensión arterial. Objetivos: establecer la incidencia de la hipertensión arterial sistémica posterior a padecer COVID-19 en pacientes de la Unidad de Medicina Familiar (UMF) No. 48. Material y métodos: es un estudio transversal, observacional y descriptivo, conformado por 3,238 pacientes con diagnóstico de COVID-19 positivo, de ambos sexos, con edades entre 18 y 70 años. Por medio de la fórmula para poblaciones infinitas se obtiene una muestra de 348 pacientes. Se realizó revisión de expedientes en el Sistema de Información de Medicina Familiar, versión 6.2, para obtención de la información correspondiente. Resultados: 27 pacientes diagnosticados con hipertensión arterial posterior al diagnóstico de COVID-19, 52% del sexo masculino y 48% del femenino, con media de edad de 39 años, 74% correspondió a enfermedad leve por COVID-19 y 26% a enfermedad moderada. Se documenta mediana de ocho días por periodo de infección por COVID-19. En el círculo femenino el promedio de la aparición de hipertensión arterial fue de 13 meses y en el masculino la media de desarrollo de hipertensión arterial posterior a COVID-19 fue de seis meses (AU)

Introduction: a new type of coronavirus that was named SARSCoV-2, responsible for the COVID-19 disease, with rapid spread in the world, due to high transmission that resulted in pandemic. There were 2'397,216 confirmed cases, with 162,956 deaths in the world, according to the WHO in April 2020. However, hypertension affects 40% of adults and means that around 250 million people suffer from high blood pressure. The WHO, according to its reports, refers that hypertension is the number one risk factor for death. One in four Mexicans suffers from high blood pressure. Objectives: to establish the incidence of systemic arterial hypertension after suffering from COVID-19 in patients of the UMF No. 48. Material and methods: it is a cross-sectional, observational and descriptive study, consisting of 3,238 patients with a positive COVID-19 diagnosis of both sexes, aged 18-70 years. Through the formula for infinite populations a sample of 348 patients is obtained. Will proceed with review of files in the Family Medicine Information System, version 6.2, to obtain the corresponding information. Results: 27 patients diagnosed with hypertension after the diagnosis of COVID-19, 52% of the male sex and 48% of the female sex, with a mean age of 39 years; 74% corresponds to a mild illness by COVID-19 and 26% to moderate disease. A median of 8 days per period of infection by COVID-19 is documented. In the female circle, the average onset of hypertension was 13 months and as for the male sex, the mean development of hypertension after COVID-19 was six months (AU)

Enzima convertidora de angiotensina homóloga (ECA2) y actividad de ROCK en la falla cardíaca experimental / ACE 2 and ROCK activity in experimental congestive heart failure

Antecedentes: La ECA2 ha mostrado ser un regulador esencial de la funcionalidad cardíaca. En un modelo experimental de insuficiencia cardíaca (IC) con Fier, modelo de coartación de aorta (COA), se encontró activación de la vía Rho-kinasa. La inhibición de esta vía con fasudil no mejoró el remodelado cardíaco ni la disfunción sistólica. Se desconoce en este modelo, si el deterioro de la función cardíaca y activación de la vía rho-kinasa se asocia con una disminución de la ECA2 cardíaca y si la inhibición de Rho-kinasa tiene un efecto sobre la expresión de ECA2. Objetivo: Nuestro objetivo es determinar si en la falla cardaca experimental por coartación aórtica, los niveles proteicos de ECA2 en el miocardio se asocian a disfunción sistólica y cual es su interacción con la actividad de ROCK en el miocardio. Métodos: Ratones C57BL6J machos de 7-8 semanas se randomizaron en 3 grupos experimentales. Grupo COA por anudación de la aorta + vehículo; Grupo COA + Fasudil (100 mg/Kg día) por bomba osmótica desde la semana 5 post-cirugía; y grupo control o Sham. Se determinaron las dimensiones y función cardíaca por ecocardiografía. Posterior a la eutanasia, se determinaron los niveles de ECA2 del VI por Western-blot y actividad de la Rho-kinasa Resultados: En los grupos COA+vehículo y COA-FAS hubo deterioro de la función cardíaca, reflejada por la reducción de la FE (47,9 ± 1,53 y 45,5 ± 2,10, p < 0,05, respectivamente) versus SHAM (68,6 ± 1,19). Además, aumentaron las dimensiones cardíacas y hubo desarrollo de hipertrofia (0,53 ± 0,02 / 0,53 ± 0,01, p < 0,05) medida por aumento de la masa cardíaca relativa respecto del grupo SHAM (0,40 ± 0,01). En los grupos COA+vehículo y COA-FAS se encontró una disminución significativa del 35% en la expresión de ECA2 cardíaca respecto al grupo control. Conclusiones: La disfunción sistólica por coartación aórtica se asocia con aumento de la actividad de Rho-kinasa y significativa disminución de la expresión de ECA2. La inhibición de Rho-kinasa no mejoró el remodelado cardíaco, la disfunción sistólica y tampoco modificó los niveles de ECA2 cardíaca.

Background: ACE2 has been described as an essential regulator of cardiac function. In an experimental model of heart failure (HF) and heart failure reduced ejection fraction (HFrEF), the aortic coarctation (COA) model, activation of the Rho-kinase pathway of cardiac remodeling was found. Inhibition of this pathway did not improve cardiac remodeling or systolic ventricular dysfunction. It is unknown in this model whether the impairment of cardiac function and activation of the rho-kinase pathway is associated with a decrease in ACE2 and whether rho-kinase inhibition has an effect on ACE2 expression. Objective: To determine if in experimental heart failure due to aortic coarctation, ACE2 protein levels in the myocardium are associated with systolic dysfunction and what is its interaction with ROCK activity in the myocardium. Methods: Male C57BL6J mice aged 7-8 weeks were divided into 3 groups and anesthetized: One group underwent COA+ vehicle; A second group COA + Fasudil (100 mg/Kg/d) by osmotic pump from week 5 post-surgery and; the third group, control(SHAM). Echocardiograms were performed to determine cardiac dimensions and systolic function. Rats were then euthanized. Ventricular expression of ACE2, activity of the Rho-kinase pathway by MYPT-1 phosphorylation, relative cardiac mass, area and perimeter of cardiomyocytes were determined by Western blot. Results: In both COA+vehicle and COA+FAS groups there was deterioration of cardiac function, reflected in the reduction of EF (47.9 ± 1.53 and 45.5 ± 2.10, p < 0.05, respectively) versus the SHAM group (68.6 ± 1.19). In addition, cardiac dimensions and hypertrophy increased (0.53 ± 0.02 / 0.53 ± 0.01, p < 0.05) due to increased relative cardiac mass compared to the SHAM group (0.40 ± 0.01). In the COA+vehicle and COA+FAS groups a significant decrease of 35% in cardiac ACE2 expression was found compared to the control group. Conclusions: Systolic dysfunction due to aortic coarctation is associated with increased Rhokinase activity and a significant decrease in ACE2 expression. Rho-kinase inhibition did not improve cardiac remodeling, systolic dysfunction, nor did it change cardiac ACE2 levels.

Potential use of renin-angiotensin-aldosterone system inhibitors to reduce COVID-19 severity.

SARS-CoV-2 infection and its clinical manifestations (COVID-19) quickly evolved to a pandemic and a global public health emergency. The limited effectivity of available treatments aimed at reducing virus replication and the lessons learned from other coronavirus infections (SARS-CoV-1 or NL63) that share the internalization process of SARS-CoV-2, led us to revisit the COVID-19 pathogenesis and potential treatments. Virus protein S binds to the angiotensin-converting enzyme 2 (ACE2) initiating the internalization process. Endosome formation removes ACE2 from the cellular membrane preventing its counter-regulative effect mediated by the metabolism of angiotensin II to angiotensin (1-7). Internalized virus-ACE2 complexes have been identified for these coronaviruses. SARS-CoV-2 presents the highest affinity for ACE2 and produces the most severe symptoms. Assuming ACE2 internalization is the trigger for COVID-19 pathogenesis, accumulation of angiotensin II can be viewed as the potential cause of symptoms. Angiotensin II is a strong vasoconstrictor, but has also important roles in hypertrophy, inflammation, remodeling, and apoptosis. Higher levels of ACE2 in the lungs explain the acute respiratory distress syndrome as primary symptoms. Most of the described findings and clinical manifestations of COVID-19, including increased interleukin levels, endothelial inflammation, hypercoagulability, myocarditis, dysgeusia, inflammatory neuropathies, epileptic seizures and memory disorders can be explained by excessive angiotensin II levels. Several meta-analyses have demonstrated that previous use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were associated with better prognosis for COVID-19. Therefore, pragmatic trials to assess the potential therapeutic benefits of renin-angiotensin-aldosterone system inhibitors should be urgently promoted by health authorities to widen the therapeutic options for COVID-19.

Tratamientos y bioterapias para COVID-19 / Therapeutics and biotherapies for covid-19

INTRODUCCIÓN: Un nuevo brote de coronavirus surgió en 2019 en Wuhan, China, causando conmoción en el sistema sanitario de todo el mundo; el Comité Internacional de Taxonomía de Virus lo denominó SARS-CoV-2, agente causante de la enfermedad COVID-19.El espectro de gravedad de la enfermedad es muy amplio: la mayoría de los pacientes no presentan gravedad, pero otros pueden desarrollar neumonías, y la insuficiencia respiratoria aguda es la causa más frecuente de mortalidad. Objetivo: analizar y desarrollar las distintas alternativas terapéuticas aportadas por la Biotecnología para tratar los síntomas de aquellos pacientes con COVID-19. Metodología: se realizó una revisión de la bibliografía disponible, a partir de enero de 2020 en PubMed, acerca de los tratamientos que se encuentran aún en ensayos clínicos y aquellos que cuentan con aprobación bajo uso de emergencia para la enfermedad COVID-19. También se realizaron búsquedas a través de Google y Google Académico para publicaciones de organismos de Salud en referencia a políticas de salud establecidas para la terapéutica durante dicha pandemia. Resultados: este trabajo aborda las nuevas alternativas terapéuticas para COVID-19 derivadas de la Biotecnología, que se encuentran tanto en uso como en etapas de ensayos clínicos comprendidos dentro del segmento de los biofármacos y las bioterapias. Se incluye un breve resumen del estatus regulatorio de entidades de salud, el mecanismo de acción de dichas terapias y características generales de cada uno. Se incluyen novedosas bioterapias que se empezaron a implementar para afrontar la pandemia. Conclusiones: la pandemia de coronavirus está poniendo a prueba el sistema sanitario internacional, para brindar soluciones tanto desde el diagnóstico y prevención como para el tratamiento de la población a fin de disminuir la mortalidad. Esto incluyó, obviamente también, al área de la Biotecnología aplicada a la salud, que ha aportado en los tres aspectos mencionados; el presente trabajo se centra en las respuestas de tipo terapéutico que ha brindado y que están comercializadas o en fases clínicas. (AU)

INTRODUCTION: A new coronavirus outbreak emerged in 2019 in Wuhan, China, causing a shock to the healthcare system around the world; the International Committee on Taxonomy of Viruses named it SARS-CoV- 2, the infectious agent of the COVID-19 disease. The spectrum of severity of the disease is very wide, most patients are not serious, but others can develop pneumonia, with acute respiratory failure being the most frequent cause of mortality. Objective: to analyze and develop the different therapeutic alternatives provided by Biotechnology dedicated to Health, to treat the symptoms of those COVID-19 patients who require it, and thus reduce mortality.Methodology: a review of the available literature from January 2020 in PubMed of the treatments that are still in clinical trials and those that have been approved under emergency use for the disease COVID-19 was performed. Searches were also carried out through Google and Google Scholar for publications of Health organizations in reference to health policies established for therapeutics during the mentioned pandemic. Results: this work addresses the new therapeutic alternatives derived from Biotechnology, which are both in use and in stages of clinical trials, to treat patients who developed COVID-19 included within the segment of biopharmaceuticals and biotherapies. A brief summary of the regulatory status of health entities, the mechanism of action of said therapies and general characteristics of each one is included. Innovative biotherapies that began to be implemented to face the pandemic are included. Conclusions: The coronavirus pandemic has driven the international health system to the test, to provide solutions both from the diagnosis, prevention and treatment of the population to reduce the mortality of patients. This obviously also included the area of Biotechnology applied to health, which has contributed in the three aspects mentioned. The present work focuses on the therapeutic responses that it has provided and that are commercialized or in clinical phases. (AU)

Uso de anticorpos monoclonais por pacientes com covid-19 interfere na concentração sérica de angiotensina II? / Does the use of monoclonal drugs by patients with COVID-19 interfere with the serum concentration of angiotensin II? / ¿El uso de fármacos monoclonales por pacientes con COVID-19 interfiere con la concentración sérica de angiotensina II?

Introdução:uma vez conhecidos os mecanismos de patogênese do SARS-CoV-2, vários métodos de tratamento para a COVID-19 foram desenvolvidos, dentre eles destaca-se o uso dos anticorpos monoclonais para o contexto de pacientes em estágios graves da doença. Objetivo: compreender se o uso dos anticorpos monoclonais para tratamento da COVID-19 grave interfere nos níveis séricos da angiotensina II. Metodologia:Para a realização dessa pesquisa foram selecionados através do DeCS e MeSH os descritores "COVID-19", "Angiotensin II" e "Antibodies, Monoclonal" e seus respectivos "entry terms" sugeridos pela base MeSH. Posteriormente,utilizando-se os operadores booleanos OR e AND, foi montada uma estratégia de busca, a qual foi utilizada nas bases de dados PUBMED, EMBASE, Web of Science, Cochrane Library e Scopus, sem restrição dedata de publicação ou idioma. Resultados:ao final do processo de seleção dos artigos, 29 foram selecionados para a leitura e análise completa. Nesta revisão, foram abordados diferentes tipos de anticorpos monoclonais, os quais foram oportunamente agrupados de acordo com o seu mecanismo de ação. Conclusão: foi possível concluir que das cinco classes de anticorpos monoclonais tratadas neste trabalho, três potencialmente podem causar alterações nos níveis séricos de angiotensina II (AU).

Introduction:once the mechanisms of pathogenesis of SARS-CoV-2 are known, several methods of treatment for COVID-19 have been developed, among them the use of monoclonal antibodies for the context of patients in severe stages of the disease. Purpose:to understand whether the use of monoclonal antibodies for the treatment of severe COVID-19 interferes with serum angiotensin II levels. Methodology:For this research were selected through DeCS and MeSH the descriptors "COVID-19", "Angiotensin II" and "Antibodies, Monoclonal" and their respective entry "Terms" suggested by the MeSH database. Subsequently, using the boolean operators OR and AND, a search strategy was set up, which was used in the databases PUBMED, EMBASE, Web of Science, Cochrane Library and Scopus, without restriction of publication date or language. Results:at the end of the article selection process, 29 were selected for reading and full analysis. In this review, different types of monoclonal antibodies were addressed, which were opportunely grouped according to their mechanism of action. Conclusion:it was possible to conclude that of the five classes of monoclonal antibodies treated in this study, three potentially can cause changes in serum levels of angiotensin II (AU).

Introducción:Una vez conocidos los mecanismos de patogénesis del SARSCoV-2, se desarrollaron variosmétodos de tratamiento para el COVID-19, entre ellos, el uso de anticuerpos monoclonales para el contexto de pacientes en fases graves de la enfermedad. Objetivo:Comprender si el uso de anticuerpos monoclonales para el tratamiento de la COVID-19 grave interfiere en los niveles séricos de angiotensina II. Metodología:Los descriptores "COVID-19", "Angiotensina II", "Anticuerpos, Monoclonales" y sus respectivos "entry terms" (términos de entrada) sugeridos por el MeSH fueron seleccionados a través de DeCS yMeSH. Posteriormente, utilizando los operadores booleanos OR y AND, se estableció una estrategia de búsqueda que se utilizó en las bases de datos PUBMED, EMBASE, Web of Science, Cochrane Library y Scopus, sin restricción de fecha de publicación ni de idioma. Resultados:Al final del proceso de selección de artículos, se seleccionaron 29 artículos para su lectura y análisis completos. En esta revisión se han abordado diferentes tipos de anticuerpos monoclonales, que se han agrupado oportunamente según su mecanismo de acción. Conclusión:Se pudo concluir que de las cinco clases de anticuerpos monoclonales tratados en este trabajo, tres pueden potencialmente causar alteraciones en los niveles séricos de angiotensina II (AU).

Renin-angiotensin system: Basic and clinical aspects-A general perspective.

The renin-angiotensin system (RAS) is one of the most complex hormonal regulatory systems, involving several organs that interact to regulate multiple body functions. The study of this system initially focused on investigating its role in the regulation of both cardiovascular function and related pathologies. From this approach, pharmacological strategies were developed for the treatment of cardiovascular diseases. However, new findings in recent decades have suggested that the RAS is much more complex and comprises two subsystems, the classic RAS and an alternative RAS, with antagonistic effects that are usually in equilibrium. The classic system is involved in pathologies where inflammatory, hypertrophic and fibrotic phenomena are common and is related to the development of chronic diseases that affect various body systems. This understanding has been reinforced by the evidence that local renin-angiotensin systems exist in many tissue types and by the role of the RAS in the spread and severity of COVID-19 infection, where it was discovered that viral entry into cells of the respiratory system is accomplished through binding to angiotensin-converting enzyme 2, which is present in the alveolar epithelium and is overexpressed in patients with chronic cardiometabolic diseases. In this narrative review, preclinical and clinical aspects of the RAS are presented and topics for future research are discussed some aspects are raised that should be clarified in the future and that call for further investigation of this system.

Implicações da COVID-19 no Sistema Cardiovascular: uma Revisão de Literatura / Implications of COVID-19 on the Cardiovascular System: a Literature Review

Introdução: O novo coronavírus da Síndrome Respiratória Aguda Grave 2 (SARS-CoV-2), responsável pela Doença do Coronavírus 2019 (COVID-19), é um vírus capaz de causar pneumonia viral, além de complicações extrapulmonares. Revisou-se conceitos básicos sobre a COVID-19, focando nos seus efeitos sobre o sistema cardiovascular. Métodos: Realizou-se revisão de literatura a partir de buscas nas bases de dados PUBMED, Scielo e LILACS entre Janeiro de 2019 a Maio de 2020, com as palavras chaves: "COVID-19" AND "Cardiovascular" e seus correlatos em português e inglês. Foram excluídos estudos repetidos, relatos de caso, estudos experimentais em animais, cartas ao editor, comentários, estudos não disponíveis em inglês ou português e os que limitavam-se à terapêutica da doença. Selecionaram-se estudos observacionais, estudos descritivos, revisões de literatura e revisões sistemáticas. Resultados: A ligação entre a injúria miocárdica e a infecção pelo novo coronavírus é consequência, em grande parte, da sua relação fisiopatológica com o receptor ECA-2, interação capaz de desequilibrar os sistemas imune e cardiovascular. As complicações mais comuns incluem arritmia, lesão cardíaca, miocardite fulminante, insuficiência cardíaca, embolia pulmonar e Coagulação Intravascular Disseminada (CIVD). Ademais, pacientes com condições cardíacas prévias possuem risco aumentado, inclusive para morbimortalidade hospitalar. Conclusão: Conclui-se que a COVID-19 é uma doença com tropismo por vários órgãos, capaz de gerar agressões em diversos sistemas, entre eles, o cardiovascular, cujos danos se devem a mecanismos que afetam tanto a estrutura do miocárdio quanto dos vasos, podendo levar ao óbito. Desta forma, há necessidade de avaliação precoce e monitoramento contínuo dos danos cardíacos.

El rol del sistema renina angiotensina a nivel cerebral / The renin-angiotensin system and the brain

El sistema renina-angiotensina-aldosterona (SRAA) y sus efectos en el flujo sanguíneo e hidrosalino han sido estudiados a nivel cardiovascular y renal. La activación del SRAA en otros órganos tiene efectos tanto locales como sistémicos, alterando la macro y microvascultura de los órganos periféricos. En el cerebro, el SRAA regula la presión arterial (PA) a través del sistema nervioso simpático. El eje enzima convertidora de angiotensina/angiotensina II/receptor de angiotensina 1 (ECA/Ang II/AT1), vía clásica, y enzima convertidora de angiotensina tipo 2/angiotensina (1-7)/receptor Mas (ECA2/Ang [1-7]/MasR), vía no clásica, modulan la respuesta simpática. Su descompensación y acumulación de Ang II propician la hipertensión neurogénica (HTN) y otras patologías vasculares. El eje aminopeptidasa/angiotensina IV/receptor de angiotensina 4 (AMN/Ang IV/AT4), exclusivo del cerebro, condiciona la microvasculatura cerebral e interviene en la cognición, la memoria y el aprendizaje. Esta revisión propone descifrar los mecanismos de regulación de la PA por el SRAA central, así como revisar sus funciones y su contribución en la neuroprotección y la cognición. (AU)

The renin-angiotensin-aldosterone (RAAS) system and its effects on blood pressure and the regulation of water and electrolyte balance have been studied focusing on the cardiovascular and renal system. The activation of RAAS in other organs has local and systemic repercussions by modeling the macro- and microvasculture of peripheral organs. The brain RAAS influence on systemic blood pressure through the sympathetic nervous system. The angiotensin converting enzyme/angiotensin II/angiotensin 1 receptor axis (ACE/AngII/AT1), classical pathway, and angiotensin converting enzyme type 2/angiotensin (1-7)/Mas receptor (ACE2/Ang (1-7)/MasR), non-classical pathway, are involved in the modulation of the sympathetic response. The imbalance of these two axes with subsequently Ang II accumulation promote neurogenic hypertension and other vascular pathologies. The aminopeptidase/angiotensin IV/angiotensin 4 receptor (AMN/Ang IV/AT4) axis, which is exclusive of the brain, acts on cerebral microvasculature and participates in cognition, memory, and learning. The aim of this review is to decipher the major central RAAS mechanisms involved in blood pressure regulation. In addition, paracrine functions of brain RAAS and its role in neuroprotection and cognition are also described in this review. (AU)

COVID-19 from a cardiovascular perspective / COVID-19 desde una perspectiva cardiovascular

Currently, myocardial injury has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). The studies also show a correlation between cardiac events and severe forms of the disease. COVID-19 begins with an early infection phase in which the virus infiltrates the lung parenchyma and proliferates. It then progresses to the pulmonary phase, where the initial inflammatory process, characterized by vasodilation, vascular permeability, and leukocyte recruitment, leads to lung damage, hypoxemia, and cardiovascular stress. The renin angiotensin aldosterone system is important in the pathophysiology of severe acute respiratory syndrome coronavirus 2 infection and in the propagation of systemic inflammation. Within this system, the pathway mediated by angiotensin-converting enzyme 2 (ACE2) produces vasodilation, cardioprotection, anti-oxidation, and anti-inflammation. Furthermore, the free form of ECA2 prevents binding of the virus to host cells and reduces its damage to the lung.

Actualmente, se ha reportado injuria miocárdica en pacientes hospitalizados por enfermedad por coronavirus 2019 (COVID-19). Los estudios, además, demuestran una correlación entre los eventos cardiacos y formas severas de la enfermedad. La COVID-19 comienza con una fase de infección temprana en la que el virus infiltra el parénquima pulmonar y prolifera. Luego progresa a la fase pulmonar, donde el proceso inflamatorio inicial, caracterizado por vasodilatación, permeabilidad vascular y reclutamiento de leucocitos, lleva a daño pulmonar, hipoxemia y estrés cardiovascular. El sistema renina angiotensina aldosterona es importante en la fisiopatología de la infección por el coronavirus 2 del síndrome respiratorio agudo grave y en la propagación de la inflamación sistémica. Dentro de este sistema, la vía mediada por la enzima convertidora de angiotensina 2 (ECA2) produce vasodilatación, cardioprotección, antioxidación y antiinflamación. Además, la forma libre de la ECA2 previene la unión del virus a las células huésped y reduce su daño al pulmón.

SARS-CoV-2 impact on oral health: a general view / Impacto del SARS-CoV-2 en la salud oral: una visión general

Abstract Coronavirus disease 2019 (COVID-19) is a new disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. China reported the first case of COVID-19 in December 2019, and a few months later, the World Health Organization declared it as a pandemic. Oral ulcers in adult patients have been associated with COVID-19. However, no cases have yet been documented in children. The angiotensin-converting enzyme-2 (ACE2) receptor has been identified in tissues of the oral cavity. Studies have identified the tongue as the site with the highest expression of ACE2, and the oral epithelium, gingival epithelium, and salivary glands as sites of lesser extent expression. ACE2 expression is lower in children and varies with age. SARS-CoV-2 in saliva has been identified in various studies, which suggests that this could be a useful sample for diagnosis. However, its presence in saliva would indicate the high risk of contagion of this fluid.

Resumen La COVID-19 es una nueva enfermedad causada por el SARS-CoV-2 (coronavirus tipo 2 del síndrome respiratorio agudo grave). El primer caso de COVID-19 se reportó en China en diciembre de 2019, y unos meses después la Organización Mundial de la Salud la declaró como una pandemia. En pacientes adultos se han asociado úlceras orales a la COVID-19; en niños aún no se han documentado casos. El receptor de la enzima convertidora de la angiotensina 2 (ECA2) se ha identificado en tejidos de la cavidad oral. Los estudios han identificado que la lengua es el sitio con mayor expresión del receptor de la ECA2, y el epitelio bucal, el epitelio gingival y las glándulas salivales lo son en menor medida. La expresión de la ECA2 es menor en los niños y va aumentando con la edad. En diversos estudios se ha identificado el SARS-CoV-2 en la saliva, lo que sugiere que podría ser una muestra útil para el diagnóstico de este virus. Sin embargo, su presencia en saliva indicaría un alto riesgo de contagio de este fluido.

Na covid-19 é real a não suspensão dos inibidores do sistema renina angiotensina aldosterona? / In covid-19, the non-suspension of inhibitors of the renina angiotensin aldosterone system is real?

A interação dos bloqueadores do sistema renina angiotensina com o SARS-CoV-2 permanece obscura. Os inibidores do sistema renina angiotensina aldosterona (IECAs) e os bloqueadores do receptor AT1 da angiotensina 2 (BRAs) são fármacos com evidências robustas para terapia farmacológica de pacientes portadores, principalmente de hipertensão arterial e insuficiência cardíaca, além de outras comorbidades cardiovasculares. Os pacientes que se beneficiam desta terapêutica são considerados grupos de risco para má evolução desta virose e não há na literatura um consenso a respeito desta questão, em vista do vírus utilizar a expressão da ECA2 para penetração no ser humano. Apesar destas considerações fisiopatológicas da biologia do vírus, as principais diretrizes recomendam não suspender a terapia dos pacientes em uso dos bloqueadores do sistema renina angiotensina aldosterona no curso da infecção com o COVID-19. Aditivamente, o estudo BRACE-CORONA trouxe evidências mais consistentes para não suspensão desses fármacos

The interaction of blockers of the renin angiotensin system with SARS-COV-2 remains unclear. Inhibitors of the renin angiotensin aldosterone system (ACE inhibitors) and angiotensin 2 AT1 receptor blockers (BRAs) are drugs with robust evidence for pharmacological therapy for patients with mainly arterial hypertension and heart failure, and other cardiovascular comorbidities. Patients who benefit from this therapy are considered groups at risk for poor evolution of this virus and the literature still does not have a consensus on this issue, in view of the virus using the expression of ECA2 to penetrate in humans. Despite these athophysiological considerations of the biology of the virus, the main guidelines recommend not to suspend therapy for patients using blockers of the renin angiotensin aldosterone system in the course of infection with COVID-19. In addition, the BRACE corona study has more consistent evidence for not suspending these drugs.

[The renin-angiotensin system and the brain]. / El rol del sistema renina angiotensina a nivel cerebral.

The renin-angiotensin-aldosterone (RAAS) system and its effects on blood pressure and the regulation of water and electrolyte balance have been studied focusing on the cardiovascular and renal system. The activation of RAAS in other organs has local and systemic repercussions by modeling the macro- and microvasculture of peripheral organs. The brain RAAS influence on systemic blood pressure through the sympathetic nervous system. The angiotensin converting enzyme/angiotensin II/angiotensin 1 receptor axis (ACE/AngII/AT1), classical pathway, and angiotensin converting enzyme type 2/angiotensin (1-7)/Mas receptor (ACE2/Ang (1-7)/MasR), non-classical pathway, are involved in the modulation of the sympathetic response. The imbalance of these two axes with subsequently Ang II accumulation promote neurogenic hypertension and other vascular pathologies. The aminopeptidase/angiotensin IV/angiotensin 4 receptor (AMN/Ang IV/AT4) axis, which is exclusive of the brain, acts on cerebral microvasculature and participates in cognition, memory, and learning. The aim of this review is to decipher the major central RAAS mechanisms involved in blood pressure regulation. In addition, paracrine functions of brain RAAS and its role in neuroprotection and cognition are also described in this review.

Overexpression of the Severe Acute Respiratory Syndrome Coronavirus-2 Receptor, Angiotensin-Converting Enzyme 2, in Diabetic Kidney Disease: Implications for Kidney Injury in Novel Coronavirus Disease 2019.

OBJECTIVES: Diabetes is associated with adverse outcomes, including death, after coronavirus disease 19 (COVID-19) infection. Beyond the lungs, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, can infect a range of other tissues, including the kidney, potentially contributing to acute kidney injury in those with severe disease. We hypothesized that the renal abundance of angiotensin-converting enzyme (ACE) 2, the cell surface receptor for SARS-CoV-2, may be modulated by diabetes and agents that block the renin-angiotensin-aldosterone system (RAAS). METHODS: The expression of ACE 2 was examined in 49 archival kidney biopsies from patients with diabetic kidney disease and from 12 healthy, potential living allograft donors using next-generation sequencing technology (RNA Seq). RESULTS: Mean ACE 2 messenger RNA was increased approximately 2-fold in diabetes when compared with healthy control subjects (mean ± SD, 13.2±7.9 vs 7.7±3.6 reads per million reads, respectively; p=0.001). No difference in transcript abundance was noted between recipients and nonrecipients of agents that block the RAAS (12.2±6.7 vs 16.2±10.7 reads per million reads, respectively; p=0.25). CONCLUSIONS: Increased ACE 2 messenger RNA in the diabetic kidney may increase the risk and/or severity of kidney infection with SARS-CoV-2 in the setting of COVID-19 disease. Further studies are needed to ascertain whether this diabetes-related overexpression is generalizable to other tissues, most notably the lungs.

Expresión génica de receptores ECA2 en cavidad bucal y glándulas salivales y su papel en la infección por SARS CoV2. Revisión de la literatura / Gene Expression of ECA2 Receptors in the Oral Cavity and Salivary Glands and Its Role in SARS CoV2 Infection. Literature Review

Resumen Los receptores ECA2 presentan una expresión génica importante en las células escamosas de la lengua y glándulas salivales, mecanismo que es conveniente para la inoculación de SARS CoV2 toda vez que busca hacer el complejo de ensamblaje mediante su glicoproteína o proteína espiga hacia el receptor ECA2 de la mucosa bucal. Una vez inoculado y favorecido por las proteasas es la llave que permite la entrada del virión en la célula huésped para su posterior replicación, aumento de carga viral y potencial desaminación e infección; los estomatólogos deben estar alerta de los mecanismos de infección en cavidad bucal para protección propia y de los pacientes que son atendidos por este personal de salud.

Abstract ECA2 receptors have an important gene expression in the squamous cells of the tongue and salivary glands, a mechanism that is convenient for the inoculation of SARS CoV2 since it seeks to make the assembly complex through its glycoprotein or spike protein towards the ECA2 receptor of the oral mucosa. Once inoculated and favored by proteases, it is the key that allows the entry of the virion into the host cell for its subsequent replication, increase of viral load and potential deamination and infection; dental professionals must be alert to the mechanisms of infection in the oral cavity for their own protection and that of the patients who are treated by this health personnel.

Enfermedad cardiovascular, oncológica y reumatológica, su comportamiento en pacientes COVID-19: Factores pronósticos, complicaciones y tratamiento

La infección por SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) puede presentar manifestaciones propias, pero también, puede exacerbar las de enfermedades preexistentes o provocar manifestaciones que simulen dichas patologías. Las enfermedades cardiovasculares, neoplásicas o reumatológicas son ejemplos de ello. Este tipo de patologías comparten factores de riesgo de mal pronóstico y de muerte por la infección, la posibilidad de desarrollar complicaciones a largo plazo, e implican un desafío al momento de instaurar medidas de seguimiento y tratamiento con requerimiento de valoración multidisciplinaria. Por ello, nuestro objetivo fue plantear las dificultades en el seguimiento a corto y largo plazo de este tipo de pacientes y evaluar cómo la pandemia afecta su tratamiento. La pandemia ha cambiado la práctica médica habitual, promoviendo nuevas formas de seguimiento de los pacientes, como la telemedicina, imponiendo jerarquizar la necesidad de atención y procedimientos presenciales, obligando a reasignar las partidas presupuestarias para poder hacer frente a la misma, con consecuencias que probablemente habrá que analizar a largo plazo.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection clinical course can present its own manifestations, but it can also exacerbate those of pre-existing diseases or cause manifestations that simulate said pathologies. Cardiovascular, cancer or rheumatological diseases are examples of this. These types of pathologies share risk factors for poor prognosis and death due to infection, the possibility of developing long-term complications, and they imply a challenge when establishing follow-up and treatment measures requiring multidisciplinary assessment. Therefore, our objective was to raise the difficulties in the short and long-term follow-up of this type of patients and to evaluate how the pandemic affects their treatment. The pandemic has changed the usual medical practice, promoting new forms of patient follow-up, such as telemedicine, imposing a hierarchy of the need for face-to-face care and procedures, forcing budget items to be reallocated to be able to deal with it, with consequences that are likely to it will have to be analyzed in the long term.

A infecção por SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pode apresentar manifestações próprias, mas também pode exacerbar aquelas de doenças pré-existentes ou causar manifestações que simulam essas patologias. Doenças cardiovasculares, neoplásicas ou reumatológicas são exemplos disso. Esses tipos de patologias compartilham fatores de risco para mau prognóstico e óbito por infecção, possibilidade de desenvolvimento de complicações em longo prazo, e representam um desafio no estabelecimento de medidas de acompanhamento e tratamento que requerem avaliação multidisciplinar. Portanto, nosso objetivo foi levantar as dificuldades no acompanhamento a curto e longo prazo desse tipo de paciente e avaliar como a pandemia afeta seu tratamento. A pandemia alterou a prática médica usual, promovendo novas formas de acompanhamento do paciente, como a telemedicina, impondo uma hierarquia da necessidade de atendimento e procedimentos presenciais, obrigando a realocação de itens orçamentários para poderem lidar com ela, com consequências que provavelmente terá que ser analisado a longo prazo.

Eje Renina Angiotensina, Enzima Convertidora de Angiotensina 2 y Coronavirus / Renin Angiotensin Axis, Angiotensin Converting Enzyme 2 and Coronavirus

Resumen: El sistema renina angiotensina aldosterona (SRAA) es el principal regulador del volumen plasmático, manteniendo la homeostasis cardiovascular e hidrosalina. En la vía clásica, la enzima convertidora de angiotensina (ECA) genera Angiotensina II (AngII), de potente efecto inflamatorio y vasoconstrictor. Esta vía clásica es a su vez regulada por la ECA2, que convierte AngII a Ang 1-7, cuyas acciones vaso dilatadoras y antiinflamatorias dan balance a los efectos de AngII. La ECA2 se ha relacionado con la patogenia de infecciones respiratorias como el virus respiratorio sincicial y el síndrome respiratorio agudo grave por coronavirus (SARS-CoV y SARS-CoV-2). Estudios recientes han demostrado que la ECA2 corresponde al principal receptor del SARS-CoV-2, que en conjunto con otros receptores como la serin proteasa TMPRSS2, permiten la fijación, fusión y entrada del virus a la célula huésped. En animales infectados por SARS-CoV se produce una caída de la concentración tisular de ECA2 y Ang 1-7, con la consiguiente sobreexpresión de AngII, y sus efectos vasoconstrictores e inflamatorios. Experimentos con ECA2 recombinante han mostrado un efecto protector frente a la sobreexpresión del SRAA en animales infectados por SARS-CoV, efecto similar al demostrado con el uso de bloquea- dores del receptor de AngII, AT1. La evidencia sobre el rol protector de ECA2 parece respaldar las recomendaciones respecto a no suspender estos medicamentos en la infección SARS-CoV-2. En este artículo presentamos el conocimiento actual sobre el rol del SRAA en la infección por SARS-CoV, a partir de conceptos fisiopatológicos, bases moleculares, y evidencia experimental y clínica.

Abstract: The renin-angiotensin-aldosterone system (RAAS) is the main plasma volume regulator, which maintains cardiovascular and hydrosaline homeostasis. In the classical pathway, the angiotensin converting enzyme (ACE) generates Angiotensin II (AngII), which is powerfully inflammatory and vasoconstrictive. This classical pathway is also regulated by ACE2, which converts AngI to Ang 1-9, and degrades AngII to Ang 1-7, whose vasodilatory and anti-inflammatory functions balance out the effects of AngII. ACE2 has been associated with the pathogenesis of respiratory infections such as RSV and severe acute respiratory syndrome coronavirus (SARS-CoV and SARS-CoV-2). Recent studies have shown that ACE2 corresponds to the main SARS-CoV-2 receptor, which together with other receptors such as the TMPRSS2, allows the virus to attach, fuse, and enter the host cell. These studies have shown that in animals infected with coronavirus there is a drop in tissue concentration of ACE2 and Ang 1-7, leading to overexpression of AngII and its vasoconstrictive and inflammatory effects. Experiments with recombinant ACE2 have shown a protective effect against overexpression of RAAS in coronavirus-infected animals, which is similar to that demonstrated with the use of AnglI receptor blockers (AT1). Evidence on the protective role of ACE2 seems to support the recommendations re garding not discontinuing these drugs in COVID-19 infection. In this article, we present the current knowledge about the role of RAAS in coronavirus infection, based on physiopathological concepts, molecular bases, and experimental and clinical evidence.

Is the cardioprotective effect of the ACE2 activator diminazene aceturate more potent than the ACE inhibitor enalapril on acute myocardial infarction in rats?

Myocardial infarction is a major cause of cardiac dysfunction. All components of the cardiac renin-angiotensin system (RAS) are upregulated in myocardial infarction. Angiotensin-converting enzyme (ACE) and ACE2 are key enzymes involved in synthesis of components of RAS and provide a counter-regulatory mechanism within RAS. We compared the cardioprotective effect of the ACE2 activator diminazene aceturate (DIZE) versus the ACE inhibitor enalapril on post acute myocardial infarction (AMI) ventricular dysfunction in rats. Adult male rats received subcutaneous injections of either saline (control) or isoproterenol (85 mg/kg) to induce AMI. Rats with AMI confirmed biochemically and by ECG, were either left untreated (AMI) or administered DIZE (AMI + DIZE) or enalapril (AMI + enalapril) daily for 4 weeks. DIZE caused a significant activation of cardiac ACE2 compared with enalapril. DIZE caused a significantly greater enhancement of cardiac hemodynamics. DIZE also caused greater reductions in heart-type fatty acid binding protein (H-FABP), ß-myosin heavy chain (ß-MYH), and in heart mass to total body mass ratio. These results indicated that activation of cardiac ACE2 by DIZE enhanced the protective axis of RAS and improved myocardial function following AMI, whereas enalapril was not sufficient to restore all cardiac parameters back to normal.

Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes.

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be renoprotective. We determined whether urinary ACE2 enzyme activity and protein levels (ELISA), as well as angiotensinogen and ACE, are elevated during clamped euglycemia (4-6 mmol·L(-1)) in patients with uncomplicated type 1 diabetes (T1D, n = 58) compared with normoglycemic controls (n = 21). We also measured the effect of clamped hyperglycemia (9-11 mmol·L(-1)) on each urinary factor in T1D patients. Urinary ACE2 activity and protein levels were higher during clamped euglycemia in T1D compared with the controls (p < 0.0001). In contrast, urinary angiotensinogen levels (p = 0.27) and ACE excretion (p = 0.68) did not differ. In response to clamped hyperglycemia in T1D, urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2 activity as well as angiotensinogen and ACE levels remained unchanged. Urinary ACE2 activity and protein expression are increased in T1D patients prior to the onset of clinical complications. Further work is required to determine the functional role of urinary ACE2 in early T1D.

Targeting angiotensin-converting enzyme 2 as a new therapeutic target for cardiovascular diseases.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes several vasoactive peptides, including angiotensin II (Ang-II; a vasoconstrictive/proliferative peptide), which it converts to Ang-(1-7). Ang-(1-7) acts through the Mas receptor to mediate vasodilatory/antiproliferative actions. The renin-angiotensin system involving the ACE-Ang-II-Ang-II type-1 receptor (AT1R) axis is antagonized by the ACE2-Ang-(1-7)-Mas receptor axis. Loss of ACE2 enhances adverse remodeling and susceptibility to pressure and volume overload. Human recombinant ACE2 may act to suppress myocardial hypertrophy, fibrosis, inflammation, and diastolic dysfunction in heart failure patients. The ACE2-Ang-(1-7)-Mas axis may present a new therapeutic target for the treatment of heart failure patients. This review is mainly focused on the analysis of ACE2, including its influence and potentially positive effects, as well as the potential use of human recombinant ACE2 as a novel therapy for the treatment cardiovascular diseases, such as hypertension and heart failure.