lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis / 医学前沿

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of atherosclerosis. Here, we investigated the role of the lncRNA growth arrest-specific 5 (lncR-GAS5) in atherogenesis. We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis, which presented as increased plaque size and reduced collagen content. Moreover, impaired autophagy was observed, as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells. By contrast, lncR-GAS5 knockdown promoted autophagy. Moreover, serine/arginine-rich splicing factor 10 (SRSF10) knockdown increased the LC3II/LC3I ratio and decreased the P62 level, thus enhancing the formation of autophagic vacuoles, autolysosomes, and autophagosomes. Mechanistically, lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium, which was reversed by the knockdown of SRSF10. Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene, SRSF10. Notably, miR-193-5p overexpression decreased plaque size and increased collagen content. Altogether, these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy. In conclusion, lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway. Thus, miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.

Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

Copper induces damage, oxidative stress and cell death in endothelium of chronic intoxicated Wistar rats / El cobre induce daño, estrés oxidativo y muerte celular en el endotelio de ratas Wistar intoxicadas

SUMMARY: Reactive Oxygen Species (ROS) are part of the functional balance of various systems, they can generate cellular damage by oxidative stress associated with disease processes such as atherosclerosis, cardiovascular disease, diabetes, and aging. Some studies report that copper induces damage to the endothelium, which could be associated with cardiovascular pathologies. This study was an experimental comparative, prospective, longitudinal, and controlled clinical trial in a murine animal model. Twenty-four male Wistar rats were included, the distribution of the groups was time-depending chronic exposition to copper, and a control group. Results show gradual alterations in the groups treated with copper: areas with loss of the endothelium, signs of disorganization of smooth muscle fibers in the tunica media, as well as areas with the fragmentation of the elastic sheets. A significant statistical difference was observed in the active- Caspase-3 analysis expression in the aortic endothelium and endothelium of the capillaries and arterioles of the lung between the control group vs 300 ppm of copper. Expression of eNOS was detected in the endothelium of the aorta and vessels of the lung. Our study shows histological changes in the walls of the great vessels of intoxicated rats with copper, and the increment of inflammatory cells in the alveoli of the study model, mainly at a high dose of copper exposition. These results will be useful to understand more about the mediators involved in the effect of copper over endothelium and cardiovascular diseases in chronic intoxication in humans.

RESUMEN: Las Especies Reactivas de Oxígeno (ROS) son parte del equilibrio funcional de varios sistemas, pueden generar daño celular por estrés oxidativo asociado a procesos patológicos como aterosclerosis, enfermedades cardiovasculares, diabetes y envejecimiento. Algunos estudios informan que el cobre induce daños en el endotelio, lo que podría estar asociado a patologías cardiovasculares. Este estudio fue un ensayo clínico experimental comparativo, prospectivo, longitudinal y controlado en un modelo animal murino. Se incluyeron veinticuatro ratas Wistar macho, la distribución de los grupos fue la exposición crónica al cobre en función del tiempo y un grupo de control. Los resultados muestran alteraciones graduales en los grupos tratados con cobre: áreas con pérdida del endotelio, signos de desorganización de las fibras musculares lisas en la túnica media, así como áreas con la fragmentación de las láminas elásticas. Se observó una diferencia estadística significativa en la expresión del análisis de caspasa-3 activa en el endotelio aórtico y el endotelio de los capilares y arteriolas del pulmón entre el grupo de control frente a 300 ppm de cobre. Se detectó expresión de eNOS en el endotelio de la aorta y los vasos del pulmón. Nuestro estudio muestra cambios histológicos en las paredes de los grandes vasos de ratas intoxicadas con cobre, y el incremento de células inflamatorias en los alvéolos del modelo de estudio, principalmente a una alta dosis de exposición de cobre. Estos resultados serán útiles para comprender más sobre los mediadores involucrados en el efecto del cobre sobre el endotelio y las enfermedades cardiovasculares en la intoxicación crónica en humanos.

Global endothelial function assessment using pulse wave analysis in hypercholesterolemia

To compare global endothelial function assessed by pulse wave analysis (PWA) using the ratio of endothelium dependent vasodilatation (EDV) to endothelium independent vasodilatation (EIV) in patients with hypercholesterolemia and controls. 92 subjects [46 hypercholesterolemics, 46 controls] were studied at standardized conditions. Baseline augmentation index (AIx) was assessed followed by the administration of 0.5 mg sublingual nitroglycerine, an endothelium independent vasodilator. AIx was assessed and the maximum change in AIx after nitroglycerine was recorded as EIV. After a washout period of 30 minutes, 400 µg of inhaled salbutamol, an endothelium dependent vasodilator was administered. AIx was assessed again and the maximum change in AIx after salbutamol was recorded as EDV. Global endothelial function was calculated as EDV:EIV ratio. EDV and EIV in patients with hypercholesterolemia compared to controls were 2.97 ± 3.95 and 6.65 ± 3.80 (p<0.001); and 13.41 ± 4.57 and 15.88 ± 4.78 (p=0.01) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls; 0.21 ± 0.38 and 0.44 ± 0.24 (p<0.001) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls. PWA is a potential clinical tool to assess global endothelial function in patients with hypercholesterole

Hepatocyte growth factor protects pulmonary endothelial barrier against oxidative stress and mitochondria-dependent apoptosis / 中华医学杂志(英文版)

BACKGROUND@#Pulmonary microvascular endothelial cells (PMVECs) were not complex, and the endothelial barrier was destroyed in the pathogenesis progress of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Previous studies have demonstrated that hepatocyte growth factor (HGF), which was secreted by bone marrow mesenchymal stem cells, could decrease endothelial apoptosis. We investigated whether mTOR/STAT3 signaling acted in HGF protective effects against oxidative stress and mitochondria-dependent apoptosis in lipopolysaccharide (LPS)-induced endothelial barrier dysfunction and ALI mice.@*METHODS@#In our current study, we introduced LPS-induced PMEVCs with HGF treatment. To investigate the effects of mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) pathway in endothelial oxidative stress and mitochondria-dependent apoptosis, mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 were, respectively, used to inhibit mTOR/STAT3 signaling. Moreover, lentivirus vector-mediated mTORC1 (Raptor) and mTORC2 (Rictor) gene knockdown modifications were introduced to evaluate mTORC1 and mTORC1 pathways. Calcium measurement, reactive oxygen species (ROS) production, mitochondrial membrane potential and protein, cell proliferation, apoptosis, and endothelial junction protein were detected to evaluate HGF effects. Moreover, we used the ALI mouse model to observe the mitochondria pathological changes with an electron microscope in vivo.@*RESULTS@#Our study demonstrated that HGF protected the endothelium via the suppression of ROS production and intracellular calcium uptake, which lead to increased mitochondrial membrane potential (JC-1 and mitochondria tracker green detection) and specific proteins (complex I), raised anti-apoptosis Messenger Ribonucleic Acid level (B-cell lymphoma 2 and Bcl-xL), and increased endothelial junction proteins (VE-cadherin and occludin). Reversely, mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 could raise oxidative stress and mitochondria-dependent apoptosis even with HGF treatment in LPS-induced endothelial cells. Similarly, mTORC1 as well as mTORC2 have the same protective effects in mitochondria damage and apoptosis. In in vivo experiments of ALI mouse, HGF also increased mitochondria structural integrity via the mTOR/STAT3 pathway.@*CONCLUSION@#In all, these reveal that mTOR/STAT3 signaling mediates the HGF suppression effects to oxidative level, mitochondria-dependent apoptosis, and endothelial junction protein in ARDS, contributing to the pulmonary endothelial survival and barrier integrity.

El endotelio como órgano diana en la fisiopatología y la terapéutica de la hipertensión arterial / The endothelium as a target organ in pathophysiology and therapy of arterial hypertension

Hemos leído con gran atención el artículo de los autores González Rey y otros, titulado: Disfunción endotelial en una etapa precoz del diagnóstico de hipertensión arterial. Resulta muy interesante el tratamiento de un tema básico de gran interés en la clínica a través del uso de biomarcadores casi siempre a la disposición de nuestros profesionales de la salud en los diferentes niveles de atención como resulta ser el caso de la microalbuminuria.1 El endotelio resulta cada vez de mayor interés para investigadores y médicos de asistencia, pues es el punto de confluencia de las enfermedades vasculares, metabólicas y neurodegenerativas, y es el primer eslabón en el desarrollo de la aterosclerosis. Se conoce que los diferentes factores involucrados en la activación y daño endotelial como las altas concentraciones de ácido úrico,2 los niveles elevados de ácidos grasos,3 el envejecimiento4 y la hiperglicemia,5 son los mismos que contribuyen a posteriori con el desarrollo y las complicaciones de la placa de ateroma. Vale destacar el aporte...(AU)

Maternal Intake of Flaxseed During Lactation and Exercise Training Protect Against Salt Overload-Induced Aortic Remodeling in Adult Offspring

Abstract Background High dietary sodium intake can induce endothelial stiffness even without changes in blood pressure. Objectives To evaluate the effects of exercise training and chronic intake of sodium chloride solution on aortic morphology of male offspring of rat dams who consumed flaxseed during lactation. Methods Female rats were fed with a control diet or a flaxseed diet during lactation. At weaning, two male offspring of each rat dam were allocated into eight groups for 180 days: four groups received a control diet e four received a flaxseed diet, with /without exercise and with/without NaCl solution supply. Aorta was collected for histomorphometric analysis. The one-way analysis of variance was used and P value < 0.05 was considered statistically significant. Results The chronic use of 1% NaCl solution led to changes in aortic histoarchitecture in the control group: increase in aortic intima-media thickness (10,4%, p<0.0001) and reduced number of elastic lamellae (-8,1%, p<0.0001). Groups of offspring of mother that consumed flaxseed during lactation, the chronic use of 1% NaCl alone did not lead to an increase in the aortic intima-media thickness. Exercise training of adult offspring increased aortic intima-media thickness (13.3%, p<0.0001), with preservation of elastic components and aortic flexibility. Conclusion Chronic salt overload caused adverse effects on the aorta of rats, and maternal consumption of the flaxseed diet during lactation protected against aortic remodeling. Int J Cardiovasc Sci. 2020; [online].ahead print, PP.0-0

Disfunción endotelial. Mecanismos e implicancias en Covid-19 / Endothelial dysfunction. Mechanisms and implications on Covid-19

Endothelium is the inner layer of vessels that separates circulating blood from the rest of the body tissues. Since its discovery, it has been involved in various functions, both systemic and organ specific. Currently, endothelial damage and failure in its functions is considered a key element in pathophysiology of various clinical scenarios, among which we may find COVID-19.Hence, it has been a target in development of strategies that seek to maintain, enhance or repair its function. The purpose of the following review is to describe what an endothelial function is about, its relation with current medical practice, and its implications in the SARS- CoV-2 pandemic. (AU)

Antioxidative Propolis From Stingless Bees (Heterotrigona Itama) Preserves Endothelium-Dependent Aortic Relaxation of Diabetic Rats: The Role of Nitric Oxide and Cyclic Guanosine Monophosphate

Propolis from stingless bees (Heterotrigona itama) is a resinous compound that exhibits antihyperglycaemia, free radical scavenging, and cardioprotective properties. The effect of propolis on diabetic vessels has not been investigated. Thus, this research aimed to determine the effect of propolis supplementation on the level of antioxidants and its mechanism of action in the aorta of diabetic rats. Male Sprague-Dawley rats were divided into five groups (n=8/group): healthy (control), untreated diabetes (DM), metformin-treated diabetes (DM+M, 300 mg/kg/day metformin), propolis-treated diabetes (DM+P, 300 mg/kg/day propolis extract) and diabetes with combined treatment (DM+M+P, dosage as former). Oral supplementation was conducted for four weeks immediately upon successful induction of diabetes by streptozotocin (60 mg/kg, intraperitoneal injection). At the end of the study, the rats were euthanised, and thoracic aorta was processed into tissue homogenates to determine the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase-1 (GPx-1) and soluble receptor for advanced glycation end-products (sRAGE). Aorta segments were harvested to examine their relaxation response towards graded concentration of acetylcholine (Ach; 10-8-10-4) M following precontraction with phenylephrine (PE; 10-6 M). Vasorelaxation towards a cumulative dose of propolis (0.01-1.00%) using PE-precontracted healthy aorta (n=6/experiments) was investigated under various simulated conditions: physiological buffer, L-NAME (10-4 M), methylene blue (10-5 M), indomethacin (10-5 M) and elevated glucose (25 mM). Propolis maintained antioxidative enzymes and sRAGE decoy molecules in the aortic tissue of the diabetic rats. The amelioration of diabetes-induced impairment of endothelium-dependent relaxation by propolis was mediated through the nitric oxide(NO)-cyclic guanosine monophosphate (cGMP) pathway. This non-clinical study reports vasoprotective property of propolis in diabetes mellitus.

Oxidonitrergic and antioxidant effects of a low molecular weight peptide fraction from hardened bean (Phaseolus vulgaris) on endothelium

About 3000 tons of beans are not used in human food due to hardening. Several studies on bean-derived bioactive peptides have shown potential to treat some diseases, including those relying on oxidative dysfunctions. We assessed the effects of peptides extracted from hardened bean Phaseolus vulgaris (PV) on reactive oxygen species (ROS) and nitric oxide (NO) production, cytotoxic and cytoprotective effects in endothelial cells, and oxidonitrergic-dependent vasodilating effects. Extract was composed by peptide fraction <3 kDa (PV3) from hardened common bean residue. PV3 sequences were obtained and analyzed with bioinformatics. Human umbilical vein endothelial cells were treated with 10, 20, 30, and 250 µg/mL PV3. Oxidative stress was provoked by 3% H2O2. Cytotoxicity and cytoprotective effects were evaluated by MTT assay, whereas, ROS and NO were quantified using DHE and DAF-FM fluorescent probes by confocal microscopy. NO- and endothelium-dependent vasodilating effects of PV3 were assessed in isolated aortic rings. We found 35 peptides with an average mass of 1.14 kDa. There were no cell deaths with 10 and 20 μg/mL PV3. PV3 at 30 μg/mL increased cell viability, while cytotoxicity was observed only with 250 μg/mL PV3. PV3 at 10 μg/mL was able to protect cells from oxidative stress. PV3 also increased NO release without causing cell death. It also reduced relative ROS production induced by H2O2. PV3 vasodilating effects relied on endothelium-dependent NO release. PV3 obtained from low-commercial-value bean displays little cytotoxicity and exerts antioxidant effects, whereas it increases endothelial NO release.

Endothelial dysfunction in COVID-19 calls for immediate attention: the emerging roles of the endothelium in inflammation caused by SARS-CoV-2 / 医学前沿

The COVID-19 pandemic has caused numerous deaths around the world. A growing body of evidence points to the important role of overwhelming inflammatory responses in the pathogenesis of COVID-19 and the effectiveness of anti-inflammation therapy against COVID-19 is emerging. In addition to affecting the lungs, COVID-19 can be a severe systemic inflammatory disease that is related to endothelial dysfunction. We are calling for closer attention to endothelial dysfunction in COVID-19 not only for fully revealing the pathogenic mechanism of COVID-19 but also for properly adjusting the strategy of clinical intervention.

Influence of height on endothelial maintenance activity: a narrative review

Recent studies have revealed an inverse association between height and cardiovascular disease. However, the background mechanism of this association has not yet been clarified. Height has also been reported to be positively associated with cancer. Therefore, well-known cardiovascular risk factors, such as increased oxidative stress and chronic inflammation, are not the best explanations for this inverse association because these risk factors are also related to cancer. However, impaired blood flow is the main pathological problem in cardiovascular disease, while glowing feeding vessels (angiogenesis) are the main characteristic of cancer pathologies. Therefore, endothelial maintenance activity, especially for the productivity of hematopoietic stem cells such as CD34-positive cells, could be associated with the height of an individual because this cell contributes not only to the progression of atherosclerosis but also to the development of angiogenesis. In addition, recent studies have also revealed a close connection between bone marrow activity and endothelial maintenance; bone marrow-derived hematopoietic stem cells contribute towards endothelial maintenance. Since the absolute volume of bone marrow is positively associated with height, height could influence endothelial maintenance activity. Based on these hypotheses, we performed several studies. The aim of this review is not only to discuss the association between height and bone marrow activity, but also to describe the potential mechanism underlying endothelial maintenance. In addition, this review also aims to explain some of the reasons that implicate hypertension as a major risk factor for stroke among the Japanese population. The review also aims to clarify the anthropological reasons behind the high risk of atherosclerosis progression in Japanese individuals with acquired genetic characteristics.

Multi-center randomized double-blind controlled study on children's anorexia (spleen-stomach disharmony) treated with Child Compound Endothelium Corneum / 中国中药杂志

Child Compound Endothelium Corneum(CCEC)has the effects in invigorating the spleen and appetizing the appetite, and dissolving the accumulation of food. The recent studies have proved that it could improve gastrointestinal motility, restore physiological gastrointestinal peristalsis, increase gastrointestinal digestive motility, and enhance appetite. This trial aimed to evaluate its clinical efficacy and safety in the treatment of children's anorexia(spleen-stomach disharmony). A total of 240 children with anorexia in line with the inclusion and exclusion criteria were selected and randomly divided into experimental group and control group, with 120 in each group. Patients in the experimental group took CCEC and Erpixing Granules simulant. Patients in the control group took Erpi-xing Granules and CCEC simulant. After 21 days of treatment, there was no statistical difference in the recovery rate of anorexia, reduced food intake, eating time, weight change, traditional Chinese medicine syndrome effect, single symptom effect, and trace element Zn recovery rate between the two groups. Based on the non-inferiority test, the experimental group was not inferior to the control group in efficacy. How-ever, the effect of CCEC in reducing appetite in children with anorexia was better than that of control drugs(P<0.05). There was no statistical difference in the incidence of adverse events and adverse reactions between the two groups during the trial. This experiment confirmed the efficacy and safety of CCEC in the treatment of children's anorexia(spleen-stomach disharmony), with a safety and re-liability in clinical application. In addition, it was a better choice for children with anorexia who were mainly manifested by reduced appetite. Meanwhile, compared with granule, chewable tablets were more convenient to take in clinic. Therefore, the efficacy and safety of CCEC for the treatment of children's anorexia(spleen-stomach disharmony) were not inferior to those of Erpixing Granules, with a safety and reliability in clnic. However, due to the small sample size of this trial, the efficacy results only show a trend. It is suggested to further carry out a large-sample-size clinical study to define the clinical advantages of CCEC.

Angioedema, endothelium, ACE2, and bradykinin - interrelationships in COVID-19: a case report / Angioedema, Endotélio, ECA2 e bradicinina - inter-relações na COVID-19: um relato de caso

ABSTRACT: COVID-19 is a new disease, whose several atypical clinical manifestations began to be observed with the evolution of the pandemic, and have been investigated to understand the pathophysiology of the disease. In this article, the objective is to describe a case of angioedema in COVID-19, considered an atypical manifestation, and rarely described in the literature. The case is of a 55-year-old patient who sought medical attention for a complaint of intermittent fever for four days. On the seventh day, he manifested angioedema in the left zygomatic projection and the right subpalpebral region. The patient had no history of angioedema earlier in life. The following day, he presented a regression of the angioedema concerning the previous day. After this period, the patient progressed well and became asymptomatic. The RT-PCR laboratory test performed on the first days of manifesting symptoms was positive for SARS-CoV-2. We correlate the onset of angioedema with the possible endotheliitis present in the disease, which has been evidenced by the observation of severe endothelial injury associated with the intracellular presence of the virus in several histopathological studies of patients with COVID-19. Also, possible deregulation of the Kininogen-Kallikrein-Kinin System (KKKS) could explain this manifestation, as SARS-CoV-2 binds to the ACE2 receptor, which is responsible for degrading kinins, such as bradykinin. (AU)

RESUMO: A COVID-19 é uma doença nova, cujas diversas manifestações clínicas atípicas começaram a ser observadas com a evolução da pandemia e foram investigadas com o objetivo de compreender a fisiopatologia da doença. Neste artigo, o objetivo é descrever um caso de angioedema no COVID-19, considerado manifestação atípica e raramente descrito na literatura. O caso é de um paciente de 55 anos que procurou atendimento médico por uma queixa de febre intermitente há quatro dias. No sétimo dia, manifestou angioedema na projeção zigomática esquerda e na região subpalpebral direita. Não tinha histórico de apresentar angioedema. No dia seguinte, ele apresentou regressão do angioedema em relação ao dia anterior. Após esse período, o paciente progrediu bem e tornou-se assintomático. O teste laboratorial de RT-PCR realizado nos primeiros dias de manifestação dos sintomas foi positivo para SARS-CoV-2. Correlacionamos o início do angioedema com a possível endotelite presente na doença, o que foi evidenciado pela observação de lesão endotelial grave associada à presença intracelular do vírus em vários estudos histopatológicos de pacientes com COVID-19. Além disso, uma possível desregulação do sistema Cininogênio-Calicreína-Cinina poderia explicar essa manifestação, já que o SARS-CoV-2 se liga ao receptor ACE2, responsável pela degradação de cininas, como a bradicinina. (AU)

COVID-19: extraño nuevo virus, endotelio y enseñanzas de una pandemia. La incertidumbre genera miedos / COVID-19: strange new virus, endothelium and lessons learned from a pandemic. Uncertainty breeds fears

La pandemia COVID-19 sorprendió a la humanidad a través de un virus desconocido y con un comportamiento "extraño": para lo cual obviamente no estábamos preparados y que por sus características después de dos meses tornó a epidemia, y tan solo un mes después en pandemia y podrá mutar finalmente a endemia. Hasta la fecha (13 agosto) ha generado 758 761 muertos con una tasa de mortalidad promedio de 3.6 % y casos totales confirmados de 21 079 074. En Colombia hay reportados a la fecha 433 805 confirmados, 14 451 fallecidos con una mortalidad de 3.26%.Se inició como tal, aparentemente el 31 de diciembre de 2019, cuando un grupo de casos de neumonía de origen desconocido se informó en Wuhan, provincia de Hubei, China. El 9 de enero de 2020, el Centro para el Control y la Prevención de Enfermedades de China informó que el agente causante es un nuevo coronavirus 2 del síndrome respiratorio agu-do grave (SARS-CoV-2). La enfermedad causada por SARS-CoV-2 fue posteriormente denominada COVID-19 por la OMS (2, 3).

História Familiar de Hipertensão Prejudica o Balanço Autonômico, mas não a Função Endotelial em Jovens Jogadores de Futebol / Family History of Hypertension Impairs the Autonomic Balance, but not the Endothelial Function, in Young Soccer Players

Resumo Fundamento A história familiar de hipertensão (HFH) é um fator de risco consistente para diversas doenças crônicas que são acompanhadas por hipertensão. Além disso, a variabilidade da frequência cardíaca (VFC) e a vasodilatação mediada pelo fluxo (VMF), ambas relacionadas ao consumo máximo de oxigênio (VO2max), são geralmente prejudicadas durante a hipertensão. Objetivo Comparar a modulação autonômica, a função endotelial (FE) e o consumo máximo de oxigênio (VO2max) de jovens atletas, separados de acordo com a história de pressão arterial (PA) dos seus pais, a fim de investigar a influência da ascendência genética nesses parâmetros. Métodos Quarenta e seis jovens jogadores de futebol do sexo masculino (18±2 anos) foram divididos em quatro grupos: 1- pai e mãe normotensos (FM-N); 2- apenas pai hipertenso (F-H); 3- apenas mãe hipertensa (M-H); 4- pai e mãe hipertensos (FM-H). Foram realizadas medições da PA, VMF, VFC e do VO2max. Na análise estatística, foi adotado o nível de significância de 5%. Resultados O desvio padrão dos intervalos RR normais (SDNN; FM-N=314±185; FM-H=182,4± 57,8), a raiz quadrada das médias quadráticas das diferenças dos intervalos R-R sucessivos (RMSSD; FM-N=248±134; FM-H=87±51), o número de diferenças entre intervalos NN sucessivos maiores que 50 ms (NN50; FM-N=367±83,4; FM-H=229±55), a proporção de NN50 dividida pelo número total de NNs (pNN50; FM-N=32,4±6,2; FM-H=21,1±5,3) e os componentes de alta (HF; FM-N=49±8,9; FM-H=35,3±12) e baixa frequência (LF; FM-N=50,9±8,9; FM-H=64,6±12), em unidades normalizadas (%), foram significativamente mais baixos no grupo FM-H do que no grupo FM-N (p<0,05). Por outro lado, a relação LF/HF (ms2) foi significativamente maior (p<0,05). Não foram encontradas diferenças significativas no VO2max e na VMF entre os grupos (p<0,05). Conclusão Em jovens jogadores de futebol do sexo masculino, a HFH desempenha um papel potencialmente importante no comprometimento do balanço autonômico, principalmente quando ambos os pais são hipertensos, mas não apresentam alterações no VO2max e na VMF. Nesse caso, há uma diminuição no controle simpatovagal, que parece preceder o dano endotelial. (Arq Bras Cardiol. 2020; 115(1):52-58)

Abstract Background The family history of hypertension (FHH) imposes consistent risk for diverse chronic diseases that are accompanied by hypertension. Furthermore, the heart rate variability (HRV) and flow-mediated dilation (FMD) are both related to maximal oxygen uptake (VO2max), and are usually impaired during hypertension Objective To compare the autonomic modulation, the endothelial function (EF) and maximum oxygen uptake (VO2max) of young athletes, separated according to their parents' blood pressure (BP) history, in order to study the influence of their genetic background on those parameters. Methods A total of 46 young male soccer players (18±2 years of age) were divided into four groups: 1-normotensive father and mother (FM-N); 2-only father was hypertensive (F-H); 3-only mother was hypertensive (M-H); 4-father and mother were hypertensive (FM-H). Measurements of BP, FMD, HRV and VO2maxwere performed. The significance level adopted in the statistical analysis was 5%. Results The standard deviation of normal RR intervals (SDNN; FM-N=314±185; FM-H=182.4± 57.8), the square root of the mean squared differences in successive RR intervals (RMSSD; FM-N=248±134; FM-H=87±51), the number of interval differences of successive NN intervals greater than 50ms (NN50; FM-N=367±83.4; FM-H=229±55), the ratio derived by dividing NN50 by the total number of NN intervals (pNN50; FM-N=32.4±6.2; FM-H=21.1±5.3) and the high (HF; FM-N=49±8.9; FM-H=35.3±12) and low-frequency (LF; FM-N=50.9±8.9; FM-H=64.6±12) components, in normalized units (%), were significantly lower in the FM-H group than in the FM-N group (p<0.05). On the other hand, the LF/HF ratio (ms2) was significantly higher (p<0.05). We found no significant difference between the groups in VO2maxand FMD (p<0.05). Conclusions In young male soccer players, the FHH plays a potentially role in autonomic balance impairment, especially when both parents are hypertensive, but present no changes in VO2maxand FMD. In this case, there is a decrease in the sympathetic-vagal control, which seems to precede the endothelial damage (Arq Bras Cardiol. 2020; 115(1):52-58)

Aspirin with or without statin in the treatment of endotheliitis, thrombosis, and ischemia in coronavirus disease

Abstract INTRODUCTION: In the genesis of coronavirus disease (COVID-19), there is a process of endotheliitis associated with thrombotic changes, no studies have reported the use of acetylsalicylic acid (ASA) as a possible therapeutic approach. Statins could potentiate the ASA therapy. METHODS: This is a series of 14 cases with a laboratory-confirmed diagnosis of COVID-19. All patients underwent the ASA therapy. Those who had risk factors for vascular disease also underwent the high-potency statin therapy. When symptoms were totally or practically resolved, patients were discharged and advised to continue medications for a complementary time, according to the clinical evolution of each patient. RESULTS: The mean age of monitored patients was 48.6 years. A total of 78.6% patients presented with at least one comorbidity, which could have contributed as a risk factor for a poor prognosis in the evolution of COVID-19. Four patients had secondary bacterial infections; three patients needed hospitalization. None of the cases progress to stage III, and all patients had remission of symptoms, with 100% survival. CONCLUSIONS: the process of endothelial dysfunction in COVID-19 involves disseminated thrombosis, initially microvascular and later expansion into larger vessels. ASA could act as a secondary prophylaxis and prevent thrombosis from developing and reaching stage III of the disease. As this was a case series, we cannot provide definitive conclusions; however, this study allows us to formulate hypotheses and support clinical trials to evaluate benefits of the ASA therapy in the treatment of COVID-19.

Suplementação de vitamina D e seus análogos para tratamento de disfunção endotelial e doenças cardiovasculares / Supplementation with vitamin D and its analogs for treatment of endothelial dysfunction and cardiovascular disease

Resumo A vitamina D (1,25-dihidroxicolecalciferol) é um pró-hormônio que tem despertado a atenção de pesquisadores após estudos demonstrarem que seus efeitos não estão restritos ao metabolismo ósseo. Assim, a presente revisão sintetiza os achados mais recentes e discute a utilidade da prescrição de vitamina D e seus análogos no tratamento e prevenção de afecções cardiovasculares e disfunção endotelial. Este trabalho consiste em uma revisão narrativa da literatura feita a partir da seleção de artigos publicados no período de 2012 a 2019. Estudos demonstraram efeitos benéficos da vitamina D3 e seus análogos sobre a função endotelial; no entanto, tais resultados mostram-se controversos, visto que pesquisas com maior amostragem e duração não encontraram redução na morbimortalidade ou nos fatores de risco cardiovascular após o uso de tais substâncias. Frente ao estado atual da arte, não existe embasamento científico claro para suplementação de vitamina D ou seus análogos para tratamento de disfunção endotelial ou doenças cardiovasculares.

Abstract Vitamin D (1,25-dihydroxycolecalciferol) is a prohormone that has attracted the interest of researchers since studies have shown that its effects are not restricted to bone metabolism. Thus, the present review summarizes the most recent findings and discusses the usefulness of prescribing vitamin D and its analogues for treatment and prevention of cardiovascular disorders and endothelial dysfunction. The paper constitutes a narrative review of the literature, selecting articles published from 2012 to 2019. Studies have shown that vitamin D3 and its analogues have beneficial effects on endothelial function, but these results are controversial, since research with larger samples and of longer duration found no reduction in morbidity and mortality or cardiovascular risk factors after use of these substances. Given the current state of the art, there is no clear scientific basis for supplementation with vitamin D or its analogues for treatment of endothelial dysfunction or cardiovascular disease.

COVID-19 grave: entenda o papel da imunidade, do endotélio e da coagulação na prática clínica / Severe COVID-19: understanding the role of immunity, endothelium, and coagulation in clinical practice

Resumo O SARS-CoV-2 é o responsável pela pandemia da COVID-19. O sistema imunológico é fator determinante no combate à infecção viral e, quando atua equilibrada e eficientemente, a doença é autolimitada e benigna. Uma parcela significativa da população, porém, apresenta resposta imune exacerbada. Os indivíduos diabéticos, hipertensos, obesos e com doenças cardiovasculares, infectados pelo vírus, apresentam maior chance de progredir para formas graves. Essas doenças estão relacionadas a processos inflamatórios crônicos e disfunção endotelial. Os receptores do tipo Toll estão presentes nas células de defesa e participam da imunopatologia de doenças cardiovasculares e metabólicas, levando à produção de citocinas pró-inflamatórias quando ativados. Devido à ação viral e à hiperativação do sistema imune, estados de hiperinflamação, hiperativação plaquetária, disfunção endotelial e hipercoagulabilidade são desenvolvidos, predispondo a tromboses venosas e arteriais. Discutiremos sobre a interação entre a COVID-19, a imunidade, o endotélio e a coagulação, como também sobre as possíveis causas de doenças cardiometabólicas impactarem negativamente na evolução da COVID-19.

Abstract SARS-CoV-2 is responsible for the COVID-19 pandemic. The immune system is a determinant factor in defense against viral infections. Thus, when it acts in a balanced and effective manner the disease is self-limited and benign. Nevertheless, in a significant proportion of the population, the immune response is exaggerated. When infected, patients with diabetes, hypertension, obesity, and cardiovascular disease are more likely to progress to severe forms. These diseases are related to chronic inflammation and endothelial dysfunction. Toll-like receptors are expressed on immune cells and play an important role in the physiopathology of cardiovascular and metabolic diseases. When activated, they can induce release of inflammatory cytokines. Hypercoagulability, hyperinflammation, platelet hyperresponsiveness, and endothelial dysfunction occur in immune system hyperactivity caused by viral activity, thereby increasing the risk of arterial and venous thrombosis. We discuss the interactions between COVID-19, immunity, the endothelium, and coagulation, as well as why cardiometabolic diseases have a negative impact on COVID-19 prognosis.